TLR4, TRIF, and MyD88 are essential for myelopoiesis and CD11c+ adipose tissue macrophage production in obese mice

• Published in: The Journal of biological chemistry Vol. 293; no. 23; pp. 8775 - 8786
• Main Authors: Griffin, Cameron, Eter, Leila, Lanzetta, Nico, Abrishami, Simin, Varghese, Mita, McKernan, Kaitlin, Muir, Lindsey, Lane, Jamie, Lumeng, Carey N., Singer, Kanakadurga
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.06.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Vesicular Transport - immunology; Adipose Tissue - immunology; Adipose Tissue - pathology; Animals; CD11c Antigen - immunology; Diet, High-Fat - adverse effects; glucose intolerance; Immunology; Inflammation - etiology; Inflammation - immunology; Inflammation - pathology; insulin resistance; macrophage; Macrophages - immunology; Macrophages - pathology; Male; metabolic syndrome; metabolism; Mice, Inbred C57BL; Mice, Obese; myeloid cell; Myeloid Differentiation Factor 88 - immunology; myeloid differentiation primary response gene 88 (MyD88); Myelopoiesis; obesity; Obesity - complications; Obesity - etiology; Obesity - immunology; Obesity - pathology; TIR domain-containing adapter-inducing interferon-B (TRIF); Toll-like receptor 4 (TLR4); Toll-Like Receptor 4 - immunology; myeloid cell; metabolic syndrome; myelopoiesis; glucose intolerance; Toll-like receptor 4 (TLR4); macrophage; metabolism; TIR domain-containing adapter-inducing interferon-B (TRIF); myeloid differentiation primary response gene 88 (MyD88); insulin resistance; obesity
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA117.001526

Obesity-induced chronic inflammation is associated with metabolic disease. Results from mouse models utilizing a high-fat diet (HFD) have indicated that an increase in activated macrophages, including CD11c+ adipose tissue macrophages (ATMs), contributes to insulin resistance. Obesity primes myeloid cell production from hematopoietic stem cells (HSCs) and Toll-like receptor 4 (TLR4), and the downstream TIR domain–containing adapter protein–inducing interferon-β (TRIF)- and MyD88-mediated pathways regulate production of similar myeloid cells after lipopolysaccharide stimulation. However, the role of these pathways in HFD-induced myelopoiesis is unknown. We hypothesized that saturated fatty acids and HFD alter myelopoiesis by activating TLR4 pathways in HSCs, differentially producing pro-inflammatory CD11c+ myeloid cells that contribute to obesity-induced metabolic disease. Results from reciprocal bone marrow transplants (BMTs) with Tlr4−/− and WT mice indicated that TLR4 is required for HFD-induced myelopoiesis and production of CD11c+ ATMs. Experiments with homozygous knockouts of Irakm (encoding a suppressor of MyD88 inactivation) and Trif in competitive BMTs revealed that MyD88 is required for HFD expansion of granulocyte macrophage progenitors and that Trif is required for pregranulocyte macrophage progenitor expansion. A comparison of WT, Tlr4−/−, Myd88−/−, and Trif−/− mice on HFD demonstrated that TLR4 plays a role in the production of CD11c+ ATMs, and both Myd88−/− and Trif−/− mice produced fewer ATMs than WT mice. Moreover, HFD-induced TLR4 activation inhibited macrophage proliferation, leading to greater accumulation of recruited CD11c+ ATMs. Our results indicate that HFD potentiates TLR4 and both its MyD88- and TRIF-mediated downstream pathways within progenitors and adipose tissue and leads to macrophage polarization.