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Identification of highly connected hub genes in the protective response program of human macrophages and microglia activated by alpha B‐crystallin
Author(s) -
Holtman Inge R.,
Bsibsi Malika,
Gerritsen Wouter H.,
Boddeke Hendrikus W. G. M.,
Eggen Bart J. L.,
van der Valk Paul,
Kipp Markus,
van Noort Johannes M.,
Amor Sandra
Publication year - 2017
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23104
Subject(s) - microglia , biology , neuroinflammation , microbiology and biotechnology , cd14 , proinflammatory cytokine , immunology , immune system , inflammation
The glial stress protein alpha B‐crystallin (HSPB5) is an endogenous agonist for Toll‐like receptor 2 in CD14 + cells. Following systemic administration, HSPB5 acts as a potent inhibitor of neuroinflammation in animal models and reduces lesion development in multiple sclerosis patients. Here, we show that systemically administered HSPB5 rapidly crosses the blood–brain barrier, implicating microglia as additional targets for HSPB5 along with peripheral monocytes and macrophages. To compare key players in the HSPB5‐induced protective response of human macrophages and microglia, we applied weighted gene co‐expression network analysis on transcript expression data obtained 1 and 4 h after activation. This approach identified networks of genes that are co‐expressed in all datasets, thus reducing the complexity of the nonsynchronous waves of transcripts that appear after activation by HSPB5. In both cell types, HSPB5 activates a network of highly connected genes that appear to be functionally equivalent and consistent with the therapeutic effects of HSPB5 in vivo , since both networks include factors that suppress apoptosis, the production of proinflammatory factors, and the development of adaptive immunity. Yet, hub genes at the core of the network in either cell type were strikingly different. They prominently feature the well‐known tolerance‐promoting programmed‐death ligand 1 as a key player in the macrophage response to HSPB5, and the immune‐regulatory enzyme cyclooxygenase‐2 (COX‐2) in that of microglia. This latter finding indicates that despite its reputation as a potential target for nonsteroidal anti‐inflammatory drugs, microglial COX‐2 plays a central role in the therapeutic effects of HSPB5 during neuroinflammation. GLIA 2017;65:460–473