dorhoi et al-2015-european journal of immunology

8/16/2019 Dorhoi Et Al-2015-European Journal of Immunology

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Eur. J. Immunol. 2015. 45: 2191–2202 HIGHLIGHTSDOI: 10.1002/eji.201545493 2191

E CI 2 01 5R evi ew S er i e s

Versatile myeloid cell subsets contribute totuberculosis-associated inammation Anca Dorhoi and Stefan H.E. Kaufmann

Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany

Tuberculosis (TB), a chronic bacterial infectious disease caused by Mycobacterium tuber-culosis (Mtb), typically affects the lung and causes profound morbidity and mortalityrates worldwide. Recent advances in cellular immunology emphasize the complexityof myeloid cell subsets controlling TB inammation. The specialization of myeloid cell

subsets for particular immune processes has tailored their roles in protection and pathol-ogy. Among myeloid cells, dendritic cells (DCs) are essential for the induction of adaptiveimmunity, macrophages predominantly harbor Mtb within TB granulomas and polymor-phonuclear neutrophils (PMNs) orchestrate lung damage. However, within each myeloidcell population, diverse phenotypes with unique functions are currently recognized,differentially inuencing TB pneumonia and granuloma functionality. More recently,myeloid-derived suppressor cells (MDSCs) have been identied at the site of Mtb infection.Along with PMNs, MDSCs accumulate within the inamed lung, interact with granuloma-residing cells and contribute to exuberant inammation. In this review, we discuss thecontribution of different myeloid cell subsets to inammation in TB by highlighting theirinteractions with Mtb and their role in lung pathology. Uncovering the manifold nature of myeloidcells in TB pathogenesis will inform the development of future immune therapiesaimed at tipping the inammation balance to the benet of the host.

Keywords: Dendritic cells Inammation Mycobacterium tuberculosis Macrophages

Neutrophils Myeloid-derived suppressor cells

Introduction

Mycobacterium tuberculosis (Mtb) continues to kill more individ-uals on this globe than any other bacterial contagious agent [1]. A breakthrough in disease pathogenesis was achieved by RobertKoch (1843–1910) in 1882, who precisely elucidated the etiology

of the disease tuberculosis (TB) [2, 3]. Since then, nearly 1 billiondeaths have been caused by TB, a higher mortality than any otherinfectious disease or war in our history [4]. Many attempts havebeen made to better understand TB pathogenesis, with the aimto create appropriate intervention measures. Despite the avail-ability of a TB vaccine, as well as drugs and diagnostics, TB hasnot been controlled satisfactorily. In 2013, 9 million new cases

Correspondence: Prof. Stefan H.E. Kaufmann and Dr. Anca Dorhoie-mail: [email protected], [email protected]

and 1.5 million deaths were reported [5]. Increasing incidences of drug-resistant TB with varying severity require novel approachesfor diagnostics, drugs, and vaccines. Accordingly, better knowl-edge of the immune response in protection and pathology of Mtbinfection is necessary.

At the core of TB pathophysiology are the inammatory

myeloid cells [6]. The evolutionary success of virulent mycobac-teria likely depends on cross-species-conserved mechanisms oper-ative in infected cells [7, 8], which allow bacillary replication andpersistence by ne-tuning pro- and anti-inammatory networks[9, 10]. While inammation-promoting events are essential at theindividual level and drive primary disease progression, balancedinammatory mechanisms appear indispensable for Mtb persis-tence within hosts with latent TB infection (LTBI) [11]. Uncov-ering Mtb’s strategies to modulate inammation at various stagesof infection represents a cornerstone for the development of dis-ease control measures. Host-directed therapy (HDT) is the most

C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu


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192 Anca Dorhoi and Stefan H.E. Kaufmann Eur. J. Immunol. 2015. 45: 2191–2202

recent approach toward TB treatment. HDT encompasses usageof host modulators, and as such, requires in-depth knowledge oncells involved in disease pathogenesis, particularly inammation[12–14]. In this review, we will focus on the diversity of myeloidcells that drive and modulate inammation in TB, and discuss howdifferent mechanisms of action could be targeted for HDT.

Mycobacterium tuberculosis and its majorcounterpart, the mononuclear phagocyte

In the most prevalent form of TB, the lung serves as source of transmission, port of entry, and site of disease manifestation. Mtbis spread by expectoration of active TB patients, who produceaerosols [15, 16]. Investigations in multiple mammalian modelsof TB, such as nonhuman primates [17], rabbits [18], mice, andguinea pigs [19, 20], have shown that promptly after Mtb entry into the lung, granulomas are formed at the site of Mtb implanta-tion in the lung parenchyma. These granulomas are composed of

mononuclear phagocytes (MPs), neutrophils (PMNs), T and B lym-phocytes [21]. As long as the granuloma is structured, it succeedsin containing Mtb. As a consequence, some 2 billion individualslive with Mtb lifelong (LTBI) without developing active TB disease.Up to 5% of Mtb-exposed adolescents and adults develop primary progressive disease and another ca. 5% of individuals with LTBIdevelop active disease, through reactivation of endogenous Mtb orreinfection with the pathogen from an exogenous source [5, 22].Clinical signs of TB are rst caused by severe impairment of lungfunction, and subsequently, by major morphological alterationsof the respiratory parenchyma. Second, most immune media-tors exert paracrine effects and orchestrate systemic inammationin TB. Macrophages, including activated and transformed MPs,represent the initiators of, and most abundant cell type within,TB granulomas [21]. Mtb is a facultative intracellular pathogenthereby replicating inside cells but also in necrotic areas of TBgranulomas [22]. Mtb is surrounded by a waxy cell wall, which isresponsible for its unique staining behavior as an acid-fast bacil-lus [23]. More importantly, this complex cell wall contributes toits effective resistance against numerous immune defense mech-anisms, for instance by interfering with phagocytosis and cellularactivation [24–26]. It is less clear whether Mtb’s waxy cell wallalso plays a role in Mtb’s slow replication and persistence [27].More obvious is the role of the cell wall in the capacity of Mtb tosurvive within MPs by interfering with phagosome maturation or

autocrine activation through cytokine production [28–32]. MPs,including blood monocytes and tissue macrophages of differenttypes, are well-known effector cells against numerous bacterial,fungal, and protozoal infections and eliminate the etiologic agentsforinstanceby producingantimicrobial molecules[33]. In TB, MPsperform a dual function, serving both as a habitat for, and effectoragainst, Mtb [32] (Table 1).

At the macrophage level, similar to the whole-organism level,a balanced inammatory response confers anti-bacterial effects with limited collateral damage. In other words, both reducedand enhanced inammation promote Mtb replication [10].

Limited inammation results in improper activation of macrophages, defective antimicrobial activity, and intracellulargrowth of the bacilli. Excessive inammation promotes recruit-ment of additional Mtb-permissive cells, cell death, and extra-cellular replication of the bacilli. Whether or not MPs restrict orallow Mtb replication depends on early innate immune sensingof bacteria [34], cell-autonomous mechanisms [35], and respon-siveness to soluble, often adaptive immune mediators, such ascytokines [36, 37]. Host sensing of Mtb by pattern recognitionreceptors (PRRs) activates various innate signaling pathways,i.e. those controlled by adaptor molecules such as myeloid dif-ferentiation factor 88 (MyD88)/IL-1 [38, 39] and spleen tyro-sine kinase/caspase recruitment domain 9 [40, 41], and resultsin cytokine release and cellular activation. These key pathways control the abundance of TB-relevant cytokines, such asTNF-α [38, 42, 43] and IL-10 [40, 41, 44] by gathering signalsfrom different PRRs. Cytosolic receptors, including the nucleotide-binding oligomerization domain (NOD) receptors (NLRs) mem-bers NOD2 and NLRP3 [45–49], absent in myeloma (AIM)-2

like receptors (ALRs) (e.g. AIM2) [50–52], and nucleic acid sen-sors (cyclic GMP-AMP synthase, cGAS; stimulator of IFN genes,STING) [53, 54], have been shown to modulate the abundanceof proinammatory cytokines (IL-1, IL-6, TNF- α ) or the release of chemokines and type 1 IFN in human and murine MPs [55–57].In addition, selected cytosolic sensors, such as STING and cGAS[53, 56–58] or the adaptor MyD88 [59], affect autophagy, acell autonomous immune response against intracellular pathogens[60]. Autophagy bypasses the block in phagosome maturation anddelivers Mtb-containing phagosomes to lysosomal compartmentstermed autophagolysosomes [60]. More recently, the aryl hydro-carbon receptor (AhR) has been identied as a cytosolic sensorfor the mycobacterial lipid, phthiocol [61]. AhR activation follow-ing Mtb infection elicits the prompt release of TNF- α , IL-6, andIL-12 in murine and human macrophages [61]. TNF- α , IL-6, andIL-12 are activators of MPs and facilitate protective T-helper type1 responses [37]. Similar effects have been observed in a murinemodel of experimental TB. Specically, AhR has been shown tolimit lung bacillary burdens and Mtb dissemination prior to initi-ation of T-cell responses, thereby emphasizing that a prototypicxenobiotic receptor is endowed with critical functions in antibac-terial immunity [61]. Multiple immune sensors have been shownto act in concert to produce cytokines, enabling autocrine activa-tion of infected macrophages. For example, the relevance of TNF-α /TNFR1 [42] and IL-1/IL-1R1 [62–65] for the anti-mycobacterial

activity of murine and human macrophages is well-established,and roles of additional cytokines, such as GM-CSF, are emerging[66] and deserve further investigation.

Regarding Mtb replication, IFN- γ represents the prototypi-cal paracrine activator produced by T cells switching on bac-tericidal programs in macrophages. The importance of IFN- γfor resistance against TB is supported by in natura evidencein humans and numerous cell-based and animal reports [67].IFN-γ has been shown to induce oxidative changes in Mtb-infectedmurine macrophages, activates the nitric oxide synthase 2 (NOS2)[68, 69], promotes antimycobacterial activities of vitamin D [70],



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Eur. J. Immunol. 2015. 45: 2191–2202 HIGHLIGHTS 2193

T a

b l e 1

. R o l e o f m y e l o i d c e l l s u b s e t s i n t u b e r c u l o s i s

C e l

l p o p u

l a t i o n / s u b p o p u l a t i o n

F u n c t i o n

M o d e l

R e f e r e n c e s

M a c r o p h a g e s

P h a g o c y t o s e M t b

, u n a b l e t o k i l l b a c t e r i a

, a l l o w M t b

p e r s i s t e n c e .

S e n s e M t b t h r o u g h m u l t i p l e P R R s ( T L R s , C L R s , A L R s , N L R s ,

C D S )

.

R e l e a s e i m m u n e m e d i a t o r s , s

u c h a s c y t o k i n e s / c h e m o k i n e s

( p r o / a n t i - i n a m m a t o r y ) , p

e p t i d e s , e

i c o s a n o i d s

, R O S / R N S .

M y c o b a c t e r i c i d a l u p o n a c t i v a t i o n .

H u m a n

p r i m a r y c e l l s e x v i v o ,

c e l l l i n e s , b

i o p s i e s

[ 3 1 ; 5 5 ; 8 8 ]

M o u s e i n v i v o , B

M D M s , c e l l

l i n e s

[ 2 4 ; 2 5 ; 2 9 ; 3 0 ; 3 8 – 4 1 ; 4 5 – 4 9 ; 5 1 – 5 4 ;

5 6 – 5

8 ; 8 3 ; 8 7 ]

N H P

[ 1 0 7 ; 1 4 5 ; 1 4 6 ]

A l l m o d e l s

[ 6 ; 2 6 ; 2 8 ; 3 2 ; 3 4 – 3

7 ; 4 2 ; 4 4 ; 5 0 ;

5 9 – 6

2 ; 7 4 ]

A l v e o l a r m a c r o p h a g e s

U p t a k e o f M t b u p o n i m p l a n t a t i o n i n a l v e o l i .

M o u s e i n v i v o

[ 8 4 ; 9 3 ; 1 0 3 ; 1 0 4 ]

A l l o w M t b r e p l i c a t i o n a n d M t b c y t o s o l i c e g r e s s i o n .

M o u s e i n / e x v i v o , h

u m a n

e x v i v o

[ 8 4 ; 1 0 9 ; 1 1 0 ]

U n d e r g o c e l l d e a t h p o s t - i n f e c t i o n a n d p r o m o t e l e u k o c y t e

r e c r u i t m e n t .


[ 8 4 ; 1 0 3 ]

M o n o c y t e s C D 1 4 + C D 1 6 –

M i g r a t e t o w a r d s M t b s t i m u l i , p r o d u c e r e a c t i v e m e t a b o l i t e s

a n d p r o - a n d a n t i - i n a m m a t o r y c y t o k i n e s , l

i m i t M t b

r e p l i c a t i o n i n t r a n s f e r m o d e l s .

H u m a n

e x v i v o , m

o u s e h y b r i d

[ 1 0 1 ]

M o n o c y t e s C D 1 4 + C D 1 6 +

S u p p o r t M t b r e p l i c a t i o n , i

n c r e a s e d f r e q u e n c y i n a c t i v e T B ,

r e f r a c t o r y t o d i f f e r e n t i a t i o n i n t o D C s .

H u m a n

e x v i v o , m

o u s e h y b r i d

[ 1 0 1 ]

M o n o c y t e s / M a c r o p h a g e s

C D 1 1 b + L y 6 C + C C R 2 +

P e r m i s s i v e f o r M t b r e p l i c a t i o n , c o n t r i b u t e t o a c t i v a t i o n o f

T - c e l l s i n d r a i n i n g l y m p h n o d e s .


[ 8 5 ; 8 6 ; 9 5 ]

C l a s s i c a l l y a c t i v a t e d m a c r o p h a g e s

( I F N - γ

/ T N F -

α )

R e s t r a i n M t b r e p l i c a t i o n .

H u m a n


c e l l l i n e s

[ 3 2 ; 7 0 ; 7 2 ]


M D M s , c e l l

l i n e s

[ 3 8 ; 4 3 ; 4 6 ; 6 8 ; 6 9 ; 7 1 ; 7 3 ]

U n d e r g o a p o p t o s i s / n e c r o s i s d e p e n d i n g o n b a c t e r i a l l o a d .

M o u s e B M D M

[ 7 5 ; 7 6 ]

A l t e r n a t i v e l y a c t i v a t e d

m a c r o p h a g e s ( I L - 4 )

R e s t r a i n m y c o b a c t e r i c i d a l m e c h a n i s m s .


M D M s

[ 7 7 ; 7 8 ]

P r e v e n t h y p e r i n a m m a t i o n i n h y p o x i c g r a n u l o m a s .


[ 1 4 8 ]

I L - 1

0 / P G E 2 - a c t i v a t e d m a c r o p h a g e s

S u p p o r t M t b r e p l i c a t i o n ( d e a c t i v a t i o n b y I L - 1

0 ) .


M D M s ,

h u m a n e x v i v o

[ 4 4 ; 8 1 ]

P r o m o t e ( I L - 1 0 ) / r e s t r a i n ( P G E 2 ) I F N I a n d c o n t r o l I L - 1 r e l e a s e

a n d c e l l d e a t h

.

M o u s e i n v i v o , H

u m a n e x v i v o

[ 8 2 ; 8 3 ]

( C o n t i n u e d

)



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T a

b l e 1

. C o n t i n u e d

C e l

l p o p u

l a t i o n / s u b p o p u l a t i o n

F u n c t i o n

M o d e l

R e f e r e n c e s

A n t i - m y c o b a c t e r i a l m a c r o p h a g e s

( v i t a m i n D / G M - C

S F / I L - 1

β )

R e s t r a i n M t b r e p l i c a t i o n b y i n d u c t i o n o f a n t i m i c r o b i a l

p e p t i d e s , b

o o s t i n g a u t o c r i n e a c t i v a t i o n a n d u n k n o w n

m e c h a n i s m s .

H u m a n

e x v i v o

[ 6 4 ; 7 0 ; 7 9 – 8 1 ]

M o u s e B M D M s , c e l l l i n e s

[ 6 3 ; 6 5 ; 6 6 ]

T r a n s f o r m e d m a c r o p h a g e s ( f o a m

y ,

e p i t h e l i o i d

, g i a n t )

P r o m o t e i n a m m a t i o n .

M o u s e i n / e x v i v o

[ 2 8 ; 1 0 2 ]

A l l o w M t b p e r s i s t e n c e .

H u m a n

e x v i v o

[ 1 2 7 ; 1 4 4 ; 1 4 9 ]

D e n

d r i t i c c e

l l s


, u n a b l e t o k i l l b a c t e r i a

.

S e n s e M t b t h r o u g h m u l t i p l e P R R s ( T L R s , C L R s , N L R s ) .

P r i m e T - c e l l s

.


u c h a s c y t o k i n e s

( p r o / a n t i - i n a m m a t o r y ) .

H u m a n

p r i m a r y c e l l s e x v i v o

[ 8 8 ; 8 9 ; 9 6 - 1 0 0 ]


M D C s

[ 3 2 ; 3 4 ; 3 6 ; 3 7 ; 4 4 ; 6 2 ; 9 3 ; 1 5 0 ; 1 5 1 ]

C D 1 1 b + C D 1 1 c +

R e l e a s e c y t o k i n e s .

M o u s e i n v i v o , e

x v i v o

[ 3 2 ; 3 6 ; 3 7 ; 8 3 ]

P r i m e T - c e l l s

.


[ 9 3 - 9 5 ]

C o n t a i n b a c t e r i a a n d a l l o w M t b c y t o s o l i c e g r e s s i o n .


[ 9 2 ; 1 0 3 ; 1 0 4 ; 1 0 9 ]

C D 1 0 3 + C D 1 1 c +



[ 1 0 8 ]

C D 1 c +


, r e l e a s e c y t o k i n e s , p

r i m e T - c e l l s

.

H u m a n

e x v i v o

[ 9 9 ]

p D C


H u m a n

e x v i v o

[ 9 9 ]

N e u t r o p

h i l s

P h a g o c y t o s e / c o n t a i n M t b

.

S e n s e M t b t h r o u g h m u l t i p l e P R R s ( T L R s , C L R s ) .

C o n t r i b u t e t o a c t i v a t i o n o f T - c e l

l s .

A n t i m y c o b a c t e r i a l a c t i v i t y

.

P r o m o t e l u n g d a m a g e , g r a n u l o m

a c a s e a t i o n a n d c a v i t a t i o n .


u c h a s c y t o k i n e s / c h e m o k i n e s

( p r o / a n t i - i n a m m a t o r y ) , r

e a c t i v e m e t a b o l i t e s , n

e u t r o p h i l

e x t r a c e l l u l a r t r a p s .

H u m a n


b i o p s i e s , B A L

[ 1 1 2 ; 1 1 8 – 1

2 0 ; 1 3 5 ; 1 3 6 ; 1 5 4 ; 1 5 5 ]

M o u s e i n v i v o , e

x v i v o

[ 8 4 ; 9 2 ; 1 0 3 ; 1 0 4 ; 1 1 5 ; 1 1 6 ; 1 2 1 –

1 2 6 ; 1 2 9 ; 1 3 4 ]

N H P

[ 1 0 7 ; 1 1 5 ]

C a t t l e

[ 1 1 7 ]

M y e

l o i d

- d e r

i v e d s u p p r e s s o r c e

l l s

( M - M

D S C /

G - M

D S C )


.

S u p p r e s s T - c e l l r e s p o n s e s .

P r o m o t e l u n g d a m a g e .


u c h a s c y t o k i n e s

( p r o / a n t i - i n a m m a t o r y ) .

H u m a n


B A L

[ 1 3 8 ; 1 3 9 ]

M o u s e i n / e x v i v o

[ 1 4 0 – 1

4 2 ]

N o t e s : A L R

, A I M 2 - l i k e r e c e p t o r ; B A L

, b r o n c h o a l v e o l a r l a v a g e B M D C

, B o n e m a r r o w - d e r i v e d d e n d r i t i c c e l l ; B M D M

, B o n e m a r r o w - d e r i v e d m a c r o p h a g e ; C D S , c y t o s o l i c D N A s e n s o r s ; C L R

, C -

t y p e l e c t i n r e c e p t o r ; D C : d e n d r i t i c c e l l ; G M - C

S F , g r a n u l o c y t e - m a c r o p h a g e c o l o n y - s t i m u l a t i n g f a c t o r ; · G - M

D S C

, G r a n u l o c y t i c m y e l o i d - d e r i v e d s u p p r e s s o r c e l l ; I F N - γ , i n

t e r f e r o n g a m m a ; I L - 1

β ,

i n t e r l e u k i n - 1

b e t a ; M - M

D S C

, m o n o c y t i c m y e l o i d - d e r i v e d s u p p r e s s o r c e l l ; M t b

, M y c o b a c t e r i u m t u b e r c u

l o s i s ; ·

N H P , n o n h u m a n p r i m a t e ; N L R

, n u c l e o t i d e - b i n d i n g o l i g o m e r i z a t i o n d o m a i n r e c e p t o r ; ·

N O D

, n u c l e o t i d e - b

i n d i n g o l i g o m e r i z a t i o n d o m a i n ; p D C

, p l a s m a c y t o i d d e n d r i t i c c e l l ; P G E 2

, p r o s t a g l a n d i n ; P R R

, p a t t e r n - r e c o g n i t i o n r e c e p t o r ; R N S

, r e a c t i v e n i t r o g e n s p e c i e s ; R O S , r e a c t i v e o x y g e n

s p e c i e s ; T L R

, T o l l - l i k e r e c e p t o r ; T N F - α , t

u m o r n e c r o s i s f a c t o r a l p h a .



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upregulates GTPases, and fosters autophagy in human and mousemacrophages [71, 72]. NOS2 is the rate-limiting enzyme for NOsynthesis, a mycobactericidal molecule [33, 73]. GTPases com-prising the MX, GBP, and IRG subfamilies are induced by IFNsand play critical roles in controlling infections with intracellularbacteria or viruses [74]. IFN- γ also modulates cell death patternsin Mtb-infected murine macrophages. IFN- γ promotes apoptosis via NO release and subsequent caspase 3/7 activation [75] orfosters necrosis [76] in heavily infected macrophages by induc-ing caspase-dependent DNA fragmentation, caspase-independentlactate dehydrogenase, and high-mobility group-box-1 proteinrelease and mitochondrial injury. Opposing effects on Mtb replica-tion have been described for IL-4 [77, 78] and IL-10 [44]. More-over, particularly in human macrophages, IL-10 has been shownto interfere with the vitamin D/cathelicidin pathway [79, 80] forcontrol of virulent mycobacteria [81]. Innate IFNs, such as IFN I,underlie more complex regulation of the anti-TB response. At theMP level, IFN I restricts antimycobacterial effector molecules, suchas IL-1 [82, 83] by promoting the release of regulatory cytokines

such as IL-10. In addition, IFN I has been shown to promote early cell death in alveolar macrophages during murine TB [84] andboosts the release of chemoattractants for MPs [84–86], thus con-tributing to the spread of infection and pulmonary inammationin infected rodents.

Macrophages [isolated from PBMCs in humansor bone marrow(BM)-derived in mice] have been extensively employed as an Mtbhost-cell model. Macrophage responses are thoroughly character-ized, including transcriptional changes upon infection [69, 87]. Apparently, macrophages share several response patterns withDCs [88, 89]. DCs are a heterogeneous population of professional APCs of primarily myeloid origin, with some subsets derived frommonocytes and others from unique precursor cells [90, 91]. Theirrole in the instruction of acquired immunity is well established[90]. Less, however, is known about the responses of DC sub-sets (e.g. conventional DCs, CD103 + mucosal DCs, plasmacytoidDCs), against Mtb, despite the fact that certain populations, suchas conventional DCs [92], have been shown to be heavily infectedby Mtb in murine models of infection (Table 1). Recent studies inrodents support a model in which partnership between various DCsubsets is required for induction of adaptive immunity. In cooper-ation, conventional DCs migrating to draining lymph nodes [93],monocyte-derived DCs, and lymph node-resident DCs present Mtbantigens to T cells [94, 95]. Human studies have largely focusedon pathogen sensing molecules expressed by DCs [96, 97] and

the capacity of monocyte-derived DCs to release cytokines uponex vivo challenge with Mtb [89, 98]. More recently, cross-talk between DC subsets, CD1c + myeloid DCs, and pDCs [99], hasbeen reported for human cells, too. In agreement with essentiality of DCs for TB control in mice, a requirement for DCs with intactmigratory features has been indicated by recent genetic investiga-tions in humans [100].

Currently, the phenotypic and functional diversity of MPsis increasingly acknowledged [91] and therefore investigationsdelineating roles of MP subsets in inammation during TB arerequired. Similar to diversity of DC subsets, various monocyte

populations (patrolling versus inammatory) [91] have beenreported. Recent studies indicate that human monocyte sub-sets differentially respond to Mtb infection (Table 1). Investiga-tions in an ex vivo and in a hybrid mouse model have shownthat CD16 + monocytes better sustain bacillary replication andmigrate faster toward Mtb compared to CD16 – monocytes [101].Moreover, disease-related macrophage phenotypes, such as trans-formed macrophages (epithelioid, foamy, giant), arise in TB [102]further emphasizing their versatility. Different animal models,such as inbred, hybrid or humanized mice, and nonhuman pri-mates, have revealed that contribution of distinct MP populationsto the pool of Mtb-infected cells varies during infection or gran-uloma stage [84, 92, 101, 103–107]. A burst size model, whichpredicts range of bacterial load per infected myeloid cell, has beenrecently established in the mouse [103]. Investigations in murinemodels have also underlined diverse roles for DC subsets. Capac-ity to produce inammatory mediators (IL-1, TNF- α , IL-12) insitu upon infection has been revealed for conventional DCs andCD103 + DCs [83, 108]. Similarly, conserved region of difference-

1(RD1)-dependent cytosolic Mtb egression has been unveiledfor various lung-residing MPs, including alveolar macrophagesand lung CD11b + CD11c + DCs [109] thus showing that cytoso-lic translocation is not occurring just ex vivo [110]. The RD1 locusharbors multiple pathogenicity factors in Mtb [111]. As exempli-ed above, efforts to ascertain functions of diverse MP populationsin TB are undertaken. The consequences for Mtb survival upon cel-lular activation, trafcking/cell-autonomous events, and precisely how MP subsets tailor inammation in TB still need to be estab-lished.

Neutrophils and myeloid regulatory cells Although MPs are generally viewed as the main host cell coun-terpart of Mtb, PMNs can also serve as bacterial reservoirs [112].These fast-responding myeloid cells have been implicated in bothprotective and destructive processes (Table 1) [113, 114]. Experi-mental murineand nonhuman primate models [84, 103, 115, 116]and cattle TB [117] indicate that PMNs are recruited early to thelung during virulent Mtb infection. Antibacterial capacities havebeen unveiled based on analysis of ex vivo cultures of PMNs [118]or total leukocytes [119, 120], but direct Mtb killing by PMNs within the lung has not been demonstrated unequivocally. Theoutcome of PMN depletion studies largely depends on the model

used, and underlines versatile roles of these myeloid cells. In resis-tant mice (C57BL/6 inbred strain), early PMN depletion indicatestheir contribution to T-cell priming [121, 122] and granulomaassembly [123]. Investigations in susceptible mice (129S2, DBA2,and I/St inbred strains), which mimic primary progressive TB–at least in part—instead reveal a detrimental, disease-promotingactivity of PMNs [84, 124, 125]. These effects areimprinted beforeonset of adaptive immunity in the 129S2 model [84]. During early Mtb infection, lung-resident cells mainly attract PMN accumula-tion into lung tissue by release of CXCR2 cognates [116, 122].CXCL1 and CXCL2 are produced by myeloid cells upon Mtb



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stimulation [116]. The main PMN chemoattractant produced early during pulmonary TB is CXCL5 [116]. It is released primarily by pneumocytes upon sensing of TLR-2 agonists from Mtb, such aslipopeptides [116]. Abundance of CXCR2 cognates follows dis-crete spatial and temporal kinetics. It largely inuences hyperin-ammation, which is characterized by heightened accumulationof leukocytes and tissue destruction [116]. A tissue chemokine sig-nature with CXCL5 playing a critical role in TB pathogenesis hasbeen identied in various murine infection models [124, 126]. At later stages of infection, additional sources, such as trans-formed macrophages, can contribute to pulmonary abundance of CXCL5, as recently suggested for active TB in humans [127]. Thetissue dynamics of PMNs and local inammation can be regu-lated, in addition, by PMN cell-intrinsic mechanisms [128, 129].Posttranscriptional regulation of PMN chemoattractants throughmicroRNA (miR), with impact on TB outcome, has been deci-phered in mice [129]. In particular, PMNs accumulate miR-223during their ontogeny, and miR-223 directly targets CXCL2, CCL3,and IL-6. This intrinsic regulation is responsible for recruitment

of PMNs into the lung during Mtb infection and modulates sys-temic availability of PMNs, likely by impacting on granulopoiesis[129]. In addition, PMNs have been shown to modulate their tis-sue dynamics by means of cellular stores of S100A8/9 proteins[115]. These proteins, also released by MPs such as macrophages[130–132], are abundant in PMN granular content and act asalarmins [133]. Serum abundance of S100A8/9 correlates withTB severity in humans and Mtb-infected experimental animals. Incontrast, IFN- γ restricts both lung accumulation of PMNs and theirsurvival [134]. The harmful role of PMNs in scenarios of failedimmunity and active TB disease suggests PMNs as amenable cellu-lar targets for HDT. While factors orchestrating the tissue dynam-ics of PMNs are increasingly characterized, less is known abouttissue fate of PMNs and their interactions with Mtb and other cellsrecruited to the lung. In vitro studies have described the propen-sity of Mtb to induce necrosis in human PMNs [135] in a processdepending on RD-1-encoded proteins [135, 136]. Whether or not,and how PMNs are disposed of within the infected lungs and theconsequences for inammation will need further investigations.

The group of myeloid cells harboring Mtb and ne-tuninginammation in TB disease has been recently expanded to includeimmature myeloid-derived suppressor cells (MDSCs), also knownas regulatory myeloid cells [137]. The association between MDSCsand inammation has long been investigated in cancer biology,but the roles of MDSCs in bacterial infections are only recently

emerging. The rst investigation on MDSCs in TB identied theseimmature cells in pleural effusions and blood of TB patients [138].Importantly, the number of MDSCs is reduced after chemother-apy, suggesting that MDSCs are part of the exuberant inamma-tory response accompanying active TB. Subsequent studies haveconrmed the systemic presence of MDSCs in TB patients [139].Experimental mouse models (TB-susceptible I/St mice) indicatethat Mtb fosters the generation of MDSCs in bone marrow, andthat susceptibility to infection and lethal inammation is associ-ated with systemic (blood and spleen) accumulation of MDSCsand the presence of MDSC-like cells in the lung parenchyma

[140]. More recently, careful analysis of MDSC kinetics in thelung of C57BL/6 and 129S2 mice has demonstrated that MDSCaccumulation is part of the general inammatory response toMtb, although their dynamics has been shown to be augmentedin a susceptible host developing primary progressive TB [141].MDSCs have been shown to restrict selected T-cell responses by mechanisms dependent on close proximity to target cells, and by release of NO [141, 142]. Similar to macrophages and PMNs,MDSCs harbor bacilli, and release proinammatory (IL-1, IL-6)and anti-inammatory (IL-10) mediators, thereby indicating theircomplex role in this disease [141]. Taken together, MDSCs repre-sent cellular components of the myeloid cell network contributingto TB pathogenesis (Table 1). Excessive frequencies of MDSCsexacerbate inammation and worsen disease outcome. Therefore,MDSCs are host defense components, which are required at opti-mal frequencies during Mtb infection. The concept of “just rightlevel” is already established in TB for selected humoral factors,such as TNF- α [143]. The benecial effects of drug-induced MDSCablation on overt inammation in TB and lung pathology [141]

indicates that MDSCs are also candidate cellular targets for HDTagainst active TB disease.

Myeloid cells in lung immunopathology

The stability of granulomas is conditioned by various mech-anisms controlling cell-intrinsic and -concerted responses.Regarding myeloid cell diversity, it is now generally accepted thatpolarized macrophages with uctuating phenotypes affect intra-granulomatous events [144]. These polarized macrophages, suchas classically (IFN- γ activated, termed M1)/alternatively (IL-4acti- vated, termed M2) activated or deactivated macrophages, releaseproinammatory (e.g. TNF- α ) or anti-inammatory (IL-10) medi-ators [145, 146]. The spectrum of activated macrophages expandsbeyond these phenotypes [147]. Polarized macrophages in addi-tion modify the metabolic milieu via enzymatic products (NO –M1, L-arginine metabolites – M2, lipids) [107, 148, 149]. Accord-ingly, macrophages can modulate granuloma outcome dependingon their phenotype, location, and interaction partners [144, 145].In contrast to macrophages, DCs are highly motile within granu-lomas, but with limited migratory capacities [150, 151]. MDSCshave been detected inside TB granulomas and classical interactionpartners for MDSCs in situ, namely T lymphocytes, have been val-idated in experimental TB in mice [141]. The ability of MDSCs to

either exit granulomas or interact with additional myeloid typesor other cells residing in granulomas needs to be explored.

The expansion of granulomas affects lung functionality by lim-iting oxygen-exchange space as fundamental respiratory function,thereby contributing to TB clinical symptomatology. TB trans-mission occurs when granulomas rupture as a consequence of caseation, allowing the entry of Mtb into airways. If Mtb entersthe blood stream and lymphatics as a result of caseation, it caninfect distant organs [15]. Enzymatic MP products, such as matrixmetalloproteases [152, 153] promote cavitation following necro-sis and caseation. PMNs are also important drivers for cavitation



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Figure 1. Schema of different myeloid celltypes with shared and specic activities intuberculosis (TB) granulomas. Caseating gran-ulomas typically present a necrotic cen-ter surrounded by mononuclear phagocytes(MPs), including macrophages (M ) in dif-ferent stages of activation and transfor-mation and dendritic cells (DCs), polymor-

phonuclear neutrophils (PMNs), myeloid reg-ulatory cells/myeloid-derived suppressor cells(MDSCs), and lymphocytes. (A) Macrophagesrepresent the major myeloid cell popula-tion containing Mycobacterium tuberculosis (Mtb)inside granulomas. Macrophages releasemulti-ple mediators upon infection or following acti-vation, such as cytokines, chemokines, andenzymaticproductsdownstream of nitric oxidesynthase 2 (NOS2) or arginase 1. Macrophagesproduce matrix metalloproteases, which con-tribute to granuloma cavitation and tissueremodeling. (B) PMN-derived factors, like gran-ular proteases, in addition participate in tis-sue liquefaction. PMNsrecruited to granulomasthrough chemokinegradients or self-containedgranular proteins (S100A8/9) foster granulomacavitation and exhibit tissue-damaging fea-tures, which promote disease exacerbation andTB transmission. (C) DCs release cytokinesand chemokines, thereby supporting in situinammatory processes. DCs are highly motilewithin granulomas and have a critical rolein stimulating antigen-specic T lymphocytes.(D) In contrast, MDSCs inhibit proliferation andcytokine release by T-cells during TB. MDSCscontain Mtb and produce selected proinam-matory and regulatory cytokines upon interac-tionwith bacteria. Frequencies of myeloid cells,their activation modes, secretory capacities,and spatiotemporal positioning inside granu-lomas and relative to other cell types, orches-trate the fate of TB granulomas, and implicitly,disease outcome, and transmission.

[154]. Early studies of human TB granulomas have suggested ahigh content of dying neutrophils [155]. More recently, resultsfrom murine TB models [153], and analyses of human specimens[112] have raised interest in how PMNs contribute to granulomacavitation. Moreover, identication of PMNs and their productsat the cavity wall and in necrotizing granulomas [154] suggest aprovocative hypothesis with a partnership between PMNs and MPsrelevant for maintenance of TB immunity, shaping intralesionalbiolm formation by Mtb and TB pathology [156]. It remainsto be established whether or not PMNs, possibly subpopulationsof PMNs, or MDSC subsets join forces to promote granuloma

caseation and cavitation.

Concluding remarks

Improvement of TB control urgently calls for faster diagnosis andprognosis, as well as more effective preventive and therapeuticmeasures. The search for biomarkers has repeatedly convergedupon myeloid cells. Transcriptional signatures [157], soluble fac-tors [115], and frequencies of selected myeloid cells, such as PMNs[158] and MDSCs [138, 141] could contribute to the assess-

ment of disease severity and inform about therapeutic options. As illustrated in this review, recent ndings have broadened ourknowledge of TB pathogenesis by emphasizing the versatile natureof myeloid populations and subpopulations contributing to TB-associated inammation (Fig. 1). Future research should aim tointegrate distinct myeloid phenotypes in inammatory interactionnetworks, uncover their dynamic features, de- or rene key inter-action hubs and assess their suitability for HDT in TB.

Acknowledgments: We thank Mary Louise Grossman for excel-lent help preparing the manuscript and Diane Schad for graph-ical assistance. This work was supported by European Union’sSeventh Framework Program project “SysteMTb” (HEALTH-F3-2009-241587); the European Union’s Horizon 2020 project“TBVAC2020” (grant no. 643381); the German Federal Min-istry of Education and Research ( Bundesministerium f ür Bildungund Forschung , BMBF) Infect ERA project “Anti-Bacterial Immune



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Regulation” (ABIR) (grant no. 031A404); and Institut M érieuxResearch Grants Programme.

Conict of interest: The authors have no commercial or nancialconict of interest.

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Abbreviations: AIM: absent in myeloma · HDT: host-directed therapy ·

LTBI: latentTB infection · MDSC: myeloid-derived suppressorcell · miR:microRNA · MP: mononuclear phagocyte · Mtb : Mycobacterium tubercu-

losis · NLR: NOD receptor · NOD: nucleotide-binding oligomerizationdomain · NOS2: nitric oxide synthase 2 · PMN: polymorphonuclear neu-trophil · STING: stimulator of IFN genes · TB: tuberculosis

Full correspondence: Prof. Stefan H. E. Kaufmann, Department of Immunology, Max Planck Institute for Infection Biology, Charit éplatz1, 10117, Berlin, GermanyFax: + 49/30-28460-501e-mail: [email protected]

Additional correspondence: Dr. Anca Dorhoi, Department of Immunology, Max Planck Institute for Infection Biology, Charit éplatz1, 10117, Berlin, Germany.e-mail: [email protected]

See all the ECI 2015 Reviews at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1521-4141/homepage/eci2015.htm

Received: 2/4/2015Revised: 23/6/2015Accepted: 29/6/2015Accepted article online: 3/7/2015


dorhoi et al-2015-european journal of immunology

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