Macrophages in immunoregulation and therapeutics

Abstract

Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers. Macrophages possess binary M1/M2 macrophage polarization settings, which perform a central role in an array of immune tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered. In addition, the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology. Moreover, they are an integral part of the tumor microenvironment, playing a part in the regulation of a wide variety of processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapeutic and checkpoint blockade immunotherapies. Herein, we discuss immune regulation in macrophage polarization and signaling, mechanical stresses and modulation, metabolic signaling pathways, mitochondrial and transcriptional, and epigenetic regulation. Furthermore, we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions. Moreover, we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis. Lastly, we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.

Fig. 1

Pathways for signaling macrophage polarization. The figure demonstrates numerous strategies essential for macrophage polarization and depicts feedback control on signaling pathways of M1 and M2. Key signal channels include IRFs, STATs, NF-κB, and SOCS. The downstream protein STAT6 is krüppel-like factor 4 (KLF-4). Also, macrophage polarization can be induced by GO (graphene oxide) towards the M1 phenotype. HA-PEI/pDNA-IL-10 or HA-PEI/pDNA-IL-4 NPs) and tuftsin-modified alginate NPs containing murine cytokine IL-10 plasmid DNA modulate programming from M1 toward M2. Similarly, enhanced expression of API, PPARγ, and CREB is mediated by cytokine receptor, fatty acid receptor, and TLR4, respectively. STAT1-STAT6 introduces the feedback control of M1 and M2, IRF5-IRF4, NF-κB-PPARγ, AP1-CREB, and AP1-PPARγ, which play a crucial role in inflammatory disease instigation, development, and termination. TLR toll-like receptor, CREB cyclic AMP-responsive element binding, NF-κB nuclear factor kappa light chain enhancer of activated B cells, STAT signal transducers and activators of transcription, PPARγ peroxisome proliferator-activated receptor γ, IRF interferon regulatory transcription factor, API apigenin

Fig. 2

The M1/M2 macrophage origin, activation, and functional basis. Macrophages are typically produced from embryonic progenitors and involve inputs from yolk sac macrophages, blood monocytes independent, and adult monocytes originating from bone marrow. Macrophage immune modulation, functional plasticity, and phenotype changes are centered on cytokines, transcription, and epigenetic deviations

Fig. 3

M1/M2 macrophage metabolic signaling pathways and immune regulation. M1 macrophage is featured by aerobic glycolysis, which leads to lactate development. The ROS and NO are produced accordingly. The PPP produces NADPH correlated with arginine synthesis and the aspartate-arginosuccinate shunt pathway (AASS). In addition, the tricarboxylic acid cycle (TCA) produces essential citrate and succinate vital to the metabolism of fatty acids and the stabilization of HIF-1α, leading to the transcription of pro-inflammatory and glycolytic genes and epigenetic alterations. On the other hand, M2 macrophage primarily generates ATP in an oxidative TCA cycle, combined with OXPHOS. This also metabolizes arginine. Similarly, the process depends on the energy sources of β-oxidation and glutamine metabolism. Also, precise signaling and immune regulation are vital in metabolic pathways, including aerobic glycolysis leading to lactate, NO, fatty acid synthesis, and glutamine pathways. Equally, acetyl-CoA, citrate, itaconate, and succinate are involved in immune regulation in the TCA cycle. Similarly, hexokinase 2 (HK-II), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and arginase 1 play their roles in immune regulation. All enzymes are shown in orange. GLUT1 glucose transporter 1, NOX2 NADPH oxidase 2, iNOS inducible nitric oxide synthase, HK hexokinase, PFK1 phosphofructo-1-kinase, PFK2 phosphofructokinase-2, LDHA lactate dehydrogenase A, MCT4 monocarboxylate transporter 4, ME1 malic enzyme, ACLY ATP-citrate lyase, FA fatty acids, FAS: fatty acid synthase, CIC citrate carrier, PDH pyruvate dehydrogenase, MDH malate dehydrogenase, FH fumarate hydratase, SDH succinate dehydrogenase, CII complex II, CAD cis-aconitate decarboxylase, ACO2 aconitase 2, IDH isocitrate dehydrogenase, SLC3a2 solute carrier family 3 member 2, LAL lysosomal acid lipase, CPT-1 carnitine palmitoyltransferase I, CD36 cluster of differentiation 36

Fig. 4

Genesis, diversity, and features of Tumor-Associated Macrophages during tumor progression and growth. Tissue-resident macrophages are derived from embryonic progenitors or HSC-derived circulating monocytes for the steady-state duration. In addition, numerous monocyte subpopulations assist in intruding myelogenous cells such as TIM, TEM, and TAM into the tumor (200). During tumor progression, TAMs may instigate through embryonic/monocytic tissue-resident macrophages activated or phenotypically altered in the course of carcinogenesis (tissue-resident TAMs) or response to tumor growth (tumor-induced TAMs). Monocytes can also directly infiltrate tumor tissue as tumor-induced effector monocyte. TAMs recruit macrophages by inducing various transcriptome and cell surface markers from a subpopulation of macrophages and embracing different pro-tumoral functions based on the TME. Such activities cause tumor initiation by inflammation, tumor progression to malignancy by stimulating angiogenesis, immunosuppression, invasion, intravasation, tumor cell extravasation at remote sites, and obstinate development of tumors. TAM tumor-associated macrophage, TEM Tie-2 [angiopoietin-2 (Ang-2)] expressing monocyte, TIM tumor-infiltrating monocyte, VEGF-A vascular endothelial growth factor A, EMAPII endothelial-monocyte-activating polypeptide II, Sema3A Semaphorin-3A. T_reg regulatory T cell, DC dendritic cell