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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Animal Parasitic Diseases Laboratory » Research » Publications at this Location » Publication #357172

Research Project: Molecular Approaches to Control Intestinal Parasites that Affect the Microbiome in Swine and Small Ruminants

Location: Animal Parasitic Diseases Laboratory

Title: Bhlhe40 mediates tissue-specific control of macrophage proliferation in homeostasis and type 2 immunity

item JARJOUR, NICHOLAS - Washington University School Of Medicine
item SCHWARZKOPF, ELIZABETH - Washington University School Of Medicine
item BRADSTREET, TARA - Washington University School Of Medicine
item SHCHUKINA, IRINA - Washington University School Of Medicine
item LIN, CHIH-CHUNG - Harvard Medical School
item HUANG, STANLEY - Case Western Reserve University (CWRU)
item LAI, CHIN-WEN - Washington University School Of Medicine
item COOK, MELISSA - Washington University School Of Medicine
item TANEJA, RESHMA - National University Of Singapore
item STAPPENBECK, THADDEUS - Washington University School Of Medicine
item RANDOLPH, GWENDALYN - Washington University School Of Medicine
item ARTYOMOV, MAXIM - Washington University School Of Medicine
item Urban, Joseph
item EDELSON, BRIAN - Consultant

Submitted to: Nature Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/6/2019
Publication Date: 6/1/2019
Citation: Jarjour, N.N., Schwarzkopf, E.A., Bradstreet, T.R., Shchukina, I., Lin, C., Huang, S., Lai, C., Cook, M.E., Taneja, R., Stappenbeck, T., Randolph, G.J., Artyomov, M.N., Urban Jr, J.F., Edelson, B.T. 2019. Bhlhe40 mediates tissue-specific control of macrophage proliferation in homeostasis and type 2 immunity. Nature Immunology. 20:687-700.

Interpretive Summary: Roundworms cause considerable morbidity in livestock that represent economic loss to agriculture. Strategies to control infection rely mostly on anti-parasitic drugs but drug resistance is a growing problem and the exploration of immune regulation during infection may provide useful benefits for integrated control strategies. Part of the problem related to morbidity is the host tissue response to roundworm infection that results in tissue destruction and disease. USDA/ARS scientists worked with others from the Washington University School of Medicine to show that immune cells called "large peritoneal macrophages -LPMs" are important in the destruction of roundworms and their elimination from infected tissues in the intestine. This is a site where digestion of nutrients and animal health are important to the growth and productive capacity of the animal. The studies showed that worms were more active and capable of greater transfer of infection via their eggs that were produced when a host factor called Bhlhe40 was deficient in the animal. This factor iscritical to a sub-population of cells, the LPMs, that contribute to immunity to the roundworm. Definition of the dynamics of this population and the mechanisms that activate and propagate their numbers will provide insight into better conditions for elimination of roundworms from infected animals through rapid self replication and enhanced immune function. This work is relevant to clinicians that study parasitic disease in livestock and humans, and for the design of more cost effective control procedures to improve health and productivity.

Technical Abstract: Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state, and can expand during type 2 immunity. Whether shared mechanisms regulate macrophage proliferation in homeostasis and disease is unclear. We found that the transcription factor Bhlhe40 was cell-intrinsically required in large peritoneal macrophages (LPMs) for self-renewal and maintenance but was not required in other resident macrophages. Bhlhe40 was selectively necessary in LPMs for proliferation, but not polarization, in response to IL-4. During a helminth infection, Bhlhe40 was required for LPM cell cycling and normal immunity to pathogen re-challenge. Bhlhe40 repressed the expression of Maf and Mafb to support proliferation of LPMs. Genomic sites bound by Bhlhe40 in LPMs included some co-bound by the macrophage lineage-determining factor PU.1, and others uniquely bound by Bhlhe40, including Maf. Our findings identify Bhlhe40 as a novel transcriptional regulator of myeloid cell-mediated immunity, controlling both self-renewal and expansion of a tissue-resident LPM population.