Alternatively activated macrophages (AAM) that accumulate during chronic T helper 2 inflammatory conditions may arise through proliferation of resident macrophages or recruitment of monocyte-derived cells. Liver granulomas that form around eggs of the helminth parasite Schistosoma mansoni require AAM to limit tissue damage. Here, we characterized monocyte and macrophage dynamics in the livers of infected CX3CR1GFP/+ mice. CX3CR1-GFP+ monocytes and macrophages accumulated around eggs and in granulomas during infection and upregulated PD-L2 expression, indicating differentiation into AAM. Intravital imaging of CX3CR1-GFP+ Ly6Clow monocytes revealed alterations in patrolling behavior including arrest around eggs that were not encased in granulomas. Differential labeling of CX3CR1-GFP+ cells in the blood and the tissue showed CD4+ T cell dependent accumulation of PD-L2+ CX3CR1-GFP+ AAM in the tissues as granulomas form. By adoptive transfer of Ly6Chigh and Ly6Clow monocytes into infected mice, we found that AAM originate primarily from transferred Ly6Chigh monocytes, but that these cells may transition through a Ly6Clow state and adopt patrolling behavior in the vasculature. Thus, during chronic helminth infection AAM can arise from recruited Ly6Chigh monocytes via help from CD4+ T cells.
References
[1]
Allen JE, Maizels RM (2011) Diversity and dialogue in immunity to helminths. Nat Rev Immunol 11: 375–388. doi: 10.1038/nri2992
[2]
Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32: 593–604. doi: 10.1016/j.immuni.2010.05.007
[3]
Van Dyken SJ, Locksley RM (2013) Interleukin-4- and Interleukin-13-Mediated Alternatively Activated Macrophages: Roles in Homeostasis and Disease. Annu Rev Immunol 31: 317–343. doi: 10.1146/annurev-immunol-032712-095906
[4]
Herbert DR, Holscher C, Mohrs M, Arendse B, Schwegmann A, et al. (2004) Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20: 623–635. doi: 10.1016/s1074-7613(04)00107-4
[5]
Anthony RM, Urban JF Jr, Alem F, Hamed HA, Rozo CT, et al. (2006) Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nature medicine 12: 955–960. doi: 10.1038/nm1451
[6]
Chen F, Liu Z, Wu W, Rozo C, Bowdridge S, et al. (2012) An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nature medicine 18: 260–266. doi: 10.1038/nm.2628
[7]
Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, et al. (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447: 1116–1120. doi: 10.1038/nature05894
[8]
Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, et al. (2011) Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480: 104–108. doi: 10.1038/nature10653
[9]
Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nature reviews Immunology 8: 958–969. doi: 10.1038/nri2448
[10]
Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, et al. (2011) Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332: 1284–1288. doi: 10.1126/science.1204351
[11]
Obata-Ninomiya K, Ishiwata K, Tsutsui H, Nei Y, Yoshikawa S, et al. (2013) The skin is an important bulwark of acquired immunity against intestinal helminths. J Exp Med 210: 2583–2595. doi: 10.1084/jem.20130761
[12]
Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, et al. (2007) The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. The Journal of experimental medicine 204: 3037–3047. doi: 10.1084/jem.20070885
[13]
Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, et al. (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317: 666–670. doi: 10.1126/science.1142883
[14]
Denney L, Kok WL, Cole SL, Sanderson S, McMichael AJ, et al. (2012) Activation of invariant NKT cells in early phase of experimental autoimmune encephalomyelitis results in differentiation of Ly6Chi inflammatory monocyte to M2 macrophages and improved outcome. Journal of immunology 189: 551–557. doi: 10.4049/jimmunol.1103608
[15]
Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 71–82. doi: 10.1016/s1074-7613(03)00174-2
[16]
Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, et al. (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20: 4106–4114. doi: 10.1128/mcb.20.11.4106-4114.2000
[17]
Serbina NV, Pamer EG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature immunology 7: 311–317. doi: 10.1038/ni1309
[18]
Hanna RN, Carlin LM, Hubbeling HG, Nackiewicz D, Green AM, et al. (2011) The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nature immunology 12: 778–785. doi: 10.1038/ni.2063
[19]
Varol C, Landsman L, Fogg DK, Greenshtein L, Gildor B, et al. (2007) Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med 204: 171–180. doi: 10.1084/jem.20061011
[20]
Yona S, Kim KW, Wolf Y, Mildner A, Varol D, et al. (2013) Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis. Immunity 38: 79–91. doi: 10.1016/j.immuni.2012.12.001
[21]
Sunderkotter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, et al. (2004) Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 172: 4410–4417. doi: 10.4049/jimmunol.172.7.4410
[22]
Tacke F, Ginhoux F, Jakubzick C, van Rooijen N, Merad M, et al. (2006) Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery. J Exp Med 203: 583–597. doi: 10.1084/jem.20052119
[23]
Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, et al. (2007) Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. The Journal of experimental medicine 204: 1057–1069. doi: 10.1084/jem.20070075
[24]
Herbert DR, Orekov T, Roloson A, Ilies M, Perkins C, et al. (2010) Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J Immunol 184: 6438–6446. doi: 10.4049/jimmunol.0902009
[25]
Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, et al. (2009) Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 5: e1000371. doi: 10.1371/journal.ppat.1000371
[26]
Broadhurst MJ, Leung JM, Lim KC, Girgis NM, Gundra UM, et al. (2012) Upregulation of Retinal Dehydrogenase 2 in Alternatively Activated Macrophages during Retinoid-dependent Type-2 Immunity to Helminth Infection in Mice. PLoS Pathog 8: e1002883. doi: 10.1371/journal.ppat.1002883
[27]
Zigmond E, Varol C, Farache J, Elmaliah E, Satpathy AT, et al. (2012) Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37: 1076–1090. doi: 10.1016/j.immuni.2012.08.026
[28]
Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L, et al. (2013) Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 153: 362–375. doi: 10.1016/j.cell.2013.03.010
[29]
Loke P, Allison JP (2003) PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A 100: 5336–5341. doi: 10.1073/pnas.0931259100
[30]
Tagliani E, Shi C, Nancy P, Tay CS, Pamer EG, et al. (2011) Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. The Journal of experimental medicine 208: 1901–1916. doi: 10.1084/jem.20110866
[31]
Loke P, Gallagher I, Nair MG, Zang X, Brombacher F, et al. (2007) Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J Immunol 179: 3926–3936. doi: 10.4049/jimmunol.179.6.3926
[32]
Barron L, Wynn TA (2011) Macrophage activation governs schistosomiasis-induced inflammation and fibrosis. European journal of immunology 41: 2509–2514. doi: 10.1002/eji.201141869
[33]
Egen JG, Rothfuchs AG, Feng CG, Winter N, Sher A, et al. (2008) Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity 28: 271–284. doi: 10.1016/j.immuni.2007.12.010
[34]
Davies SJ, Grogan JL, Blank RB, Lim KC, Locksley RM, et al. (2001) Modulation of blood fluke development in the liver by hepatic CD4+ lymphocytes. Science 294: 1358–1361. doi: 10.1126/science.1064462
[35]
Lin SL, Castano AP, Nowlin BT, Lupher ML Jr, Duffield JS (2009) Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol 183: 6733–6743. doi: 10.4049/jimmunol.0901473
[36]
Egawa M, Mukai K, Yoshikawa S, Iki M, Mukaida N, et al. (2013) Inflammatory Monocytes Recruited to Allergic Skin Acquire an Anti-inflammatory M2 Phenotype via Basophil-Derived Interleukin-4. Immunity 38: 570–580. doi: 10.1016/j.immuni.2012.11.014
[37]
Charo IF, Taubman MB (2004) Chemokines in the pathogenesis of vascular disease. Circulation research 95: 858–866. doi: 10.1161/01.res.0000146672.10582.17
[38]
Pearce EJ, MacDonald AS (2002) The immunobiology of schistosomiasis. Nat Rev Immunol 2: 499–511. doi: 10.1038/nri843
[39]
Rutitzky LI, Lopes da Rosa JR, Stadecker MJ (2005) Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol 175: 3920–3926. doi: 10.4049/jimmunol.175.6.3920
[40]
Gajewski TF, Goldwasser E, Fitch FW (1988) Anti-proliferative effect of IFN-gamma in immune regulation. II. IFN-gamma inhibits the proliferation of murine bone marrow cells stimulated with IL-3, IL-4, or granulocyte-macrophage colony-stimulating factor. Journal of immunology 141: 2635–2642.
[41]
Matheu MP, Cahalan MD, Parker I (2011) Immunoimaging: studying immune system dynamics using two-photon microscopy. Cold Spring Harbor protocols 2011 pdb top99. doi: 10.1101/pdb.top99
[42]
Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, et al. (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325: 612–616. doi: 10.1126/science.1175202
