Plasticity and crosstalk of mesenchymal stem cells and macrophages in immunomodulation in sepsis

Abstract

Sepsis is a multisystem disease characterized by dysregulation of the host immune response to infection. Immune response kinetics play a crucial role in the pathogenesis and progression of sepsis. Macrophages, which are known for their heterogeneity and plasticity, actively participate in the immune response during sepsis. These cells are influenced by the ever-changing immune microenvironment and exhibit two-sided immune regulation. Recently, the immunomodulatory function of mesenchymal stem cells (MSCs) in sepsis has garnered significant attention. The immune microenvironment can profoundly impact MSCs, prompting them to exhibit dual immunomodulatory functions akin to a double-edged sword. This discovery holds great importance for understanding sepsis progression and devising effective treatment strategies. Importantly, there is a close interrelationship between macrophages and MSCs, characterized by the fact that during sepsis, these two cell types interact and cooperate to regulate inflammatory processes. This review summarizes the plasticity of macrophages and MSCs within the immune microenvironment during sepsis, as well as the intricate crosstalk between them. This remains an important concern for the future use of these cells for immunomodulatory treatments in the clinic.

Keywords: crosstalk; immunomodulation; macrophage; mesenchymal stem cell; plasticity; sepsis.

Figure 1

Kinetics of the immune response in sepsis. In sepsis, after the recognition of PRRs by host cells, innate and adaptive immune responses are activated to clear pathogens and may cause a systemic inflammatory response syndrome (SIRS). Concurrently, a compensatory anti-inflammatory response (CARS) prevents excessive inflammation, maintaining immune balance and reducing tissue damage. However, immune dysregulation can lead to a constant state of imbalance, resulting in hyperinflammation or immunosuppression, thereby exacerbating sepsis progression and prognosis.

Figure 2

Polarization of macrophages and MSCs. (A) Polarization of macrophages; (B) Polarization of MSCs. TLR, Toll-like receptor; MCSF, macrophage colony-stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; LPS, lipopolysaccharide; PGE2, prostaglandin-2; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; MSCs, mesenchymal stem cells.

Figure 3

Immunomodulatory plasticity of macrophages and MSCs in sepsis. In sepsis, monocyte-derived macrophages and tissue-resident macrophages polarize to M1 macrophages, while MSCs polarize to MSC1 in response to pathogen recognition. M1 macrophages release proinflammatory cytokines to combat pathogens and induce intense inflammation and tissue injury. MSCs stimulated by proinflammatory cytokines and Th1-derived IFN-γ upregulate iNOS expression to suppress the immune response by inhibiting T-cell function. In addition, MSCs can polarize to MSC1 in response to TLR4 recognition, thereby promoting inflammation. Under anti-inflammatory conditions, macrophages polarize towards the M2 phenotype, while MSCs downregulate iNOS expression, thereby promoting inflammation. Furthermore, MSCs can polarize to MSC2 in response to TLR3 recognition, suppressing inflammation. (TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α; iNOS, inducible nitric oxide synthase; DAMPs, damage associated molecular patterns; HLA-DR, human leukocyte antigen DR; NO, nitric oxide).

Figure 4

Crosstalk between macrophages and MSCs in sepsis. (A) The effects of MSCs on macrophages through direct cell contact, paracrine signalling, efferocytosis, mitochondria transfer and message delivery via MSCs-EVs. These interactions reprogram macrophage phenotype and function during sepsis. (B) M1 and M2 macrophages exert different effects on MSCs, including promoting apoptosis, direct recruitment and promoting IL-1β expression, affecting MSC osteogenic differentiation. Additionally, M1 and M2 macrophages modify the immunoregulatory function of MSCs by releasing proinflammatory and anti-inflammatory cytokines, creating distinct immune environments in sepsis. (PGE2, Prostaglandin-2; TGF-β, transforming growth factor-β; MSCs, mesenchymal stem cells; MSC-Abs, mesenchymal stem cell-derived apoptosis bodies; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; MEVs, macrophage derived extracellular vesicles; iNOS, inducible nitric oxide synthase).