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Review
. 2022 Sep 26;11(19):3001.
doi: 10.3390/cells11193001.

Macrophages, Chronic Inflammation, and Insulin Resistance

He Li  1 , Ya Meng  1 , Shuwang He  2 , Xiaochuan Tan  1 , Yujia Zhang  1 , Xiuli Zhang  1 , Lulu Wang  3 , Wensheng Zheng  1
Affiliations
Review

Macrophages, Chronic Inflammation, and Insulin Resistance

He Li et al. Cells. .

Abstract

The prevalence of obesity has reached alarming levels, which is considered a major risk factor for several metabolic diseases, including type 2 diabetes (T2D), non-alcoholic fatty liver, atherosclerosis, and ischemic cardiovascular disease. Obesity-induced chronic, low-grade inflammation may lead to insulin resistance, and it is well-recognized that macrophages play a major role in such inflammation. In the current review, the molecular mechanisms underlying macrophages, low-grade tissue inflammation, insulin resistance, and T2D are described. Also, the role of macrophages in obesity-induced insulin resistance is presented, and therapeutic drugs and recent advances targeting macrophages for the treatment of T2D are introduced.

Keywords: chronic inflammation; insulin resistance; macrophages; molecular mechanism; obesity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Obesity induces macrophage infiltration and insulin resistance in adipose tissue, liver, and skeletal muscle. In the lean state, tissue-resident M2 macrophages in adipose tissue secrete anti-inflammatory factors such as IL-1 and IL-10 to maintain an insulin-sensitive environment. During obesity, increased levels of nutrients result in adipocyte hypertrophy and apoptosis. Proinflammatory mediators result in M2 macrophage polarization into the M1 state, which triggers adipose tissue chronic inflammation. Other metabolic tissues, including skeletal muscle and liver, are also influenced by increased cytokine production and macrophage recruitment, resulting in lower glucose uptake in skeletal muscle and higher glucose production in the liver, fueling the insulin resistance state further.
Figure 2
Figure 2
Cytokines regulate insulin sensitivity in insulin target cells. Activation of the insulin receptor leads to tyrosine phosphorylation of IRS-1 and initiates insulin signal transduction. Activation of TLR2/4 and TNFR results in the promotion of NF-κB and JNK signaling pathways. The serine kinases IKK and JNK-1 could reduce the signaling of IRS-1 and impair downstream insulin signaling. Moreover, the activation of IKK causes phosphorylation and degradation of IκB; thus, NF-κB could translocate into the nucleus. JNK promotes the formation of the AP-1 transcription factor, which in turn transactivates inflammatory gene expression by NF-κB and AP-1, further contributing to insulin resistance. PPAR-γ suppresses the NF-κB transcription activity and upregulates IRS protein, which favors the improvement insulin sensitivity. LTB4 promotes JNK activation through BLT-1 and leads to subsequent IRS-1 serine phosphorylation, ultimately promoting cellular insulin resistance. Gal-3 directly inhibits the insulin receptor and impairs all the major steps in the insulin signaling pathway. Additionally, IL6 induces SOCS-3 and leads to proteasomal degradation of IRS-1 through binding to the IL-6 receptor. IL-1β stimulates the translocation of NF-κB to the nucleus through IL-1R1, promoting inflammatory gene expression. Also, lipid metabolites, including FFAs, ceramides, and DAG, activate the PKC to impair IRS-1, which directly interfere with insulin signaling.
Figure 3
Figure 3
Cytokine stimulation leads to classical activation and alternative activation of macrophages. IL4 and IL13 activate macrophages to M2 polarization state through STAT6 and stimulate anti-inflammatory gene expression. M2 macrophages participate in Th2 response, anti-inflammatory, antigen endocytosis, and tumor promotion. On the other hand, when stimulated by LPS, IL-1β, and TNF-α, macrophages activate the inflammatory signaling cascades mediated by JNK and NF-κB, which stimulate M1 polarization of macrophages and inflammatory gene expression. M1 macrophages are involved in Th1 response, proinflammatory process, tissue damage, and so on.
Figure 4
Figure 4
Role of the immune system in regulating polarization of macrophage and insulin resistance. In an insulin-sensitive state, ILC2 cells produce IL-5 and IL-13 to assist in the maturation and recruitment of eosinophils. Eosinophils and Treg cells promote the activation of M2 macrophages in the adipose tissue via IL-4 and IL-13 secretion. M2 macrophages and Treg cells secrete anti-inflammatory factors such as IL-10 to maintain insulin sensitivity in lean adipose tissue. In the obese state, recruitment of monocytes and differentiation into M1 macrophages are induced significantly. Mast cells produce IL-6 to trigger T-cell and M1 macrophage activation. Neutrophils contribute to M1 polarization of macrophages and impaired insulin signaling via the production of elastase, IL-6, and IL-1β. CD4+ and CD8+ T cells stimulate M1 macrophage polarization by secreting IFN-γ, IL17, and chemokines. B cells release NF-κB, IL6, and IgG that further contribute to M1 macrophage polarization and insulin resistance.
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Grants and funding

This work was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-026, 2022-I2M-JB-012,2022-I2M-2-002).