Macrophage polarization and MRSA infection in burned mice

Abstract

Mortality associated with Staphylococcus aureus infection remains high during the sub-acute phase of burn injury. In this study, we aimed to improve antibacterial resistance of sub-acutely burned mice through macrophage polarization. Sepsis did not develop in mice at the sub-acute phase of 5% total body surface area (TBSA) burn after being infected with methicillin-resistant S. aureus (MRSA), and M1 macrophages (interleukin (IL)-10IL-12 inducible nitric oxide synthase Mφ) were isolated from these mice. In contrast, predominantly M2b macrophages (C-C motif chemokine ligand 1 (CCL1)IL-10IL-12 Mφ) were isolated from mice with >15% TBSA burn, and all of these mice died after the same MRSA infection. Comparing NOD scid gamma mice inoculated with Mφ with 25% TBSA burns, all mice treated with CCL1 antisense oligodeoxynucleotide (ODN) survived after MRSA infection, whereas all untreated mice given the same infection died within 4 days. CCL1 antisense ODN has been characterized as a specific polarizer of M2bMφ. M1Mφ were isolated from MRSA-infected mice with 25% TBSA burn after treatment with CCL1 antisense ODN, and these mice were shown to be resistant against a lethal dose of MRSA infection. M1Mφ were also isolated from 25% TBSA-burned mice infected with MRSA when the ODN was administered therapeutically, and subsequent sepsis was effectively controlled in these mice. These results indicate that the M2bMφ polarizer is beneficial for controlling MRSA infection in mice at the sub-acute phase of severe burn injury.

M2b macrophage polarization and its roles in diseases

“…Interestingly, CCL1 released from M2b cells is essentially required for maintaining the properties of M2b monocytes/macrophages . Growing evidences have shown that CCL1 is the specific molecular identifier of M2b and may serve as a marker for identifying M2b from the other subtypes of macrophages …”

“…Under normal physiologic conditions, monocytes in the blood retain a quiescent state (M0: CCL1 − , CD163 − , CD14 + ) . During infection, monocytes/macrophages acquire the M1 phenotype (IL‐10 − , IL‐12 + , iNOS + , CXCL9 + ), which is a major effector cells for the first line of host antibacterial defense . Mild burn injury (5% of the total body surface area [TBSA] burn) induces M1 macrophage polarization .…”

“…Despite a strong phagocytic capacity, M2b macrophages are not the main cells responsible for killing bacteria . Moreover, M2b monocytes/macrophages not only have no antibacterial effect, but also they increase susceptibility to opportunistic pathogens such as S. aureus , methicillin‐resistant S. aureus (MRSA) (M2b: CCL1 + , CD163 + , CD64 − , CD209 − ), E. faecalis , C. albicans (M2b: IL‐10 + , TNF‐α + , MR + , Dectin‐1 + ), and K. pneumonia . Some studies have shown that M1 macrophages are not easily generated in immunosuppressed hosts (such as severely burned patients) with a predominance of M2b .…”

“…The most likely explanation for this phenomenon is that M2b inhibits macrophage conversion from quiescent M0 to M1, resulting in a decrease in anti‐pathogens (Fig. ) …”

“…Based on the expression profile of cytokines, chemokines, and other secreted factors, M2b macrophages regulate the breadth and depth of the immune response and the inflammatory reaction . In cancer and infectious diseases, M2b macrophages promote tumor development and parasite, bacterial, and fungal infections by blunting the immune and inflammatory response . Moreover, M2b macrophages can reduce spinal cord injury (SCI) and myocardial ischemia/reperfusion (IR) injury, and contribute to recovery from these injuries .…”