Pushing the envelope: Immune mechanism and application landscape of macrophage-activating lipopeptide-2

Abstract

Mycoplasma fermentans can cause respiratory diseases, arthritis, genitourinary tract infections, and chronic fatigue syndrome and have been linked to the development of the human immunodeficiency virus. Because mycoplasma lacks a cell wall, its outer membrane lipoproteins are one of the main factors that induce inflammation in the organism and contribute to disease development. Macrophage-activating lipopeptide-2 (MALP-2) modulates the inflammatory response of monocytes/macrophages in a bidirectional fashion, indirectly enhances the cytotoxicity of NK cells, promotes oxidative bursts in neutrophils, upregulates surface markers on lymphocytes, enhances antigen presentation on dendritic cells and induces immune inflammatory responses in sebocytes and mesenchymal cells. MALP-2 is a promising vaccine adjuvant for this application. It also promotes vascular healing and regeneration, accelerates wound and bone healing, suppresses tumors and metastasis, and reduces lung infections and inflammation. MALP-2 has a simple structure, is easy to synthesize, and has promising prospects for clinical application. Therefore, this paper reviews the mechanisms of MALP-2 activation in immune cells, focusing on the application of MALP-2 in animals/humans to provide a basis for the study of pathogenesis in Mycoplasma fermentans and the translation of MALP-2 into clinical applications.

Keywords: Mycoplasma fermentans; application; immunoreaction; inflammation; macrophage-activating lipopeptide-2.

Figure 1

MALP-2 activates immune cells. Clockwise: (A) MALP-2 activated monocytes release cytokines and chemokines, causing monocytes to exhibit a bipolar fibroblast-like morphology. (B) MALP-2 enhanced the phagocytosis of PMN and activated PMN to secrete IL-8 and MIP-1β. (C) MALP-2 induced dendritic cells to release cytokines and stimulated upregulation of expression of co-stimulatory molecules and others. (D) MALP-2 activated NK cells to release IFN-γ and TNF-α in the presence of COX-2 inhibitors, enhancing CD107a degranulation from NK cells. (E) MALP-2 induced the release of cytokines and chemokines and promotes lactate dehydrogenase release from damaged UCMSCs. (F) MALP-2 activated B cells and increases the expression of their surface activation markers, such as CD25, which significantly enhances B cell proliferation.

Figure 2

Potential signaling pathway induced by MALP-2 in THP1 cells. MALP-2 induces MMP-9 expression in THP-1 cells via the MAPKs pathway; MALP-2 can decrease ABCA1 expression and subsequent cholesterol efflux through activation of the TLR2/NF-κB/ZNF202 signaling pathway in THP-1 macrophages; The cytoplasmic adaptor Mal recruits the TLR2/6 heterodimer in response to MALP-2 stimulation. c-Src, Btk, Mal and MyD88 form a physical complex to activate PI3K, which further induces Nrf2 translocation to the nucleus and binds to the ARE-site to stimulate HO-1 expression.

Figure 3

Application of MALP-2. (A) MALP-2 inhibited the growth of pancreatic cancer tissue in patients and prevented lung metastases in mice, and MALP-2, combined with CD40, significantly suppressed melanoma growth in mice. (B) MALP-2 can enhance the immune response and act as an adjuvant when used with various vaccines. (C) MALP-2 recruited macrophages to release cytokines to induce vascular endothelial cell proliferation and promote angiogenesis; MALP-2 stimulated endothelial cells to release NO and cytokines. (D) MALP-2 stimulates skin fibroblasts to release cytokines and chemokines, thereby recruiting granulocytes, monocytes, and macrophages to the wound; MALP-2 induces fibroblasts to proliferate and stimulates recruited immune cells to release growth factors for wound healing. (E) MALP-2 increases bone resorption activity of osteoclasts by inducing the release of PGE and IL-6, which in turn accelerates bone healing in mouses.