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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02019

Function of CSF1 and IL34 in macrophage homeostasis, inflammation and cancer

 Ali A. Zarrin1*, Flavius Martin2, Wei Lin1,  Daqi Xu3, Cary Austin3, Patrick Caplazi3, Kate Senger3, Yonglian Sun3, Zhiyu Huang3, Juan Zhang3, Surinder Jeet3, Carrie Looney3, Eric Suto3, Donghong Yan3, Cesar Corzo3, Kai Barck3, Vineela Ganham3, Justin Lesch3, Wei-ching Liang3, Gerald Nakamura3, Elaine Mai3, Hai Ngu3, Judy Mak3, Patricia Almeida3,  Judy Young3, Yongmei Chen3,  Dinah Misner3,  Lori Lin3, Dimitry Danilenko3, Paula Katavolos3, Estelle Doudemont3, Hirdesh Uppal3, Lauri Diehl3, Min Xu3, Jeffrey Eastham-Anderson3, Katherine Bao3, Azadeh Hadadianpour3, Mary Keir3, Rick Carano3, Sharmila Rajan3, Robby Weimer3, WYne Lee3, Jason Devoss3, Mercedesz Balazs3, Kevin Walsh3, Kathila Alatsis3 and Yan Wu3
  • 1Immunology Discovery, Genentech, United States
  • 2Amgen (United States), United States
  • 3Genentech, Inc., United States

Colony stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal via the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited to the central nervous system and skin during development. However, the roles of IL34 and CSF1 at homeostasis or in the context of inflammatory diseases or cancer in wild-type mice have not been clarified in vivo. By neutralizing CSF1 and/or IL34 in adult mice, we identified that they play important roles in macrophage differentiation, specifically in steady state microglia, Langerhans cells and kidney macrophages. In several inflammatory models, neutralization of both CSF1 and IL34 contributed to maximal disease protection. However, in a myeloid cell-rich tumor model, CSF1 but not IL34, was required for tumor-associated macrophage accumulation and immune homeostasis. Analysis of human inflammatory conditions reveals IL34 upregulation that may account for the protection requirement of IL34 blockade. Furthermore, evaluation of IL34 and CSF1 blockade treatment during Listeria infection reveal no substantial safety concerns. Thus, IL34 and CSF1 play non-redundant roles in macrophage differentiation, and therapeutic intervention targeting IL34 and/or CSF1 may provide an effective treatment in macrophage driven immune-pathologies.

Keywords: CSF1 and Il34 inhibition , Cancer, Inflammation, macrophage, monocyte

Received: 18 Jun 2019; Accepted: 09 Aug 2019.

Edited by:

Cordula M. Stover, University of Leicester, United Kingdom

Reviewed by:

Mihaela Gadjeva, Harvard Medical School, United States
Francesco Borriello, Boston Children's Hospital, Harvard Medical School, United States  

Copyright: © 2019 Zarrin, Martin, Lin, Xu, Austin, Caplazi, Senger, Sun, Huang, Zhang, Jeet, Looney, Suto, Yan, Corzo, Barck, Ganham, Lesch, Liang, Nakamura, Mai, Ngu, Mak, Almeida, Young, Chen, Misner, Lin, Danilenko, Katavolos, Doudemont, Uppal, Diehl, Xu, Eastham-Anderson, Bao, Hadadianpour, Keir, Carano, Rajan, Weimer, Lee, Devoss, Balazs, Walsh, Alatsis and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Ali A. Zarrin, Immunology Discovery, Genentech, South San Francisco, United States, ZARRIN.ALI@GENE.COM