Proinflammatory and anti-inflammatory signaling describes the dynamic balance among mediators that initiate, amplify, restrain, and resolve immune responses. Mesenchymal stromal/stem cells (MSCs) and MSC-derived products can respond to inflammatory cues and release cytokines, chemokines, lipid mediators, metabolites, enzymes, and extracellular vesicles that alter host-cell behavior. Reported pathways include prostaglandin E2, indoleamine 2,3-dioxygenase, transforming growth factor-beta, interleukin-10, nitric-oxide-related pathways in some species, and others. These signals are context-dependent rather than uniformly suppressive. Source, manufacturing, priming, dose, timing, tissue environment, and recipient immune state can change both magnitude and direction of the response.
Figure 1 placeholder — Proinflammatory and anti-inflammatory signaling
T-cell regulation
T-cell regulation includes effects on activation, proliferation, differentiation, trafficking, cytokine production, and the balance among effector and regulatory T-cell populations. In experimental systems, MSCs can reduce selected T-cell proliferative responses and influence Th1, Th17, cytotoxic, and regulatory T-cell phenotypes through soluble mediators, cell contact, metabolic pathways, and antigen-presenting-cell interactions. These effects depend on inflammatory licensing and experimental context. Reduced proliferation in vitro does not establish clinically meaningful immunosuppression, and changes in circulating T-cell subsets do not necessarily demonstrate the mechanism responsible for a clinical outcome.
Figure 2 placeholder — T-cell regulation
Macrophage phenotype
Macrophage phenotype refers to the functional state of macrophages across a broad continuum of inflammatory, reparative, antimicrobial, metabolic, and tissue-remodeling programs. The traditional M1/M2 shorthand can be useful conceptually but oversimplifies in-vivo macrophage biology. MSCs, apoptotic MSCs, EVs, cytokines, metabolites, and phagocytic interactions can alter macrophage transcription, cytokine release, efferocytosis, antigen presentation, and tissue-repair behavior. Macrophage reprogramming is therefore a plausible host-mediated mechanism, but phenotype should be defined by measured functions and markers rather than assigned from a small marker panel.
Figure 3 placeholder — Macrophage phenotype
Dendritic-cell modulation
Dendritic-cell modulation involves effects on differentiation, maturation, antigen processing, antigen presentation, migration, costimulatory molecules, and cytokine production. MSC-associated signals can reduce selected maturation markers or alter dendritic-cell cytokine profiles in experimental models, potentially influencing downstream T-cell responses. The outcome depends on dendritic-cell subset, maturation state, inflammatory environment, and product characteristics. A change in one surface marker does not establish tolerogenic function, and suppression of an in-vitro dendritic-cell assay does not prove clinically beneficial immune tolerance.
Figure 4 placeholder — Dendritic-cell modulation
Natural-killer-cell effects
Natural-killer-cell effects include changes in NK-cell activation, proliferation, cytokine production, receptor expression, and cytotoxic function. MSCs can inhibit selected NK-cell responses in some experimental conditions through soluble factors and cell-contact mechanisms, while activated NK cells can also recognize and lyse MSCs. This bidirectional interaction means that the recipient immune environment can influence persistence and biological activity of administered cells. NK-cell suppression should not be assumed to be uniformly desirable because NK cells contribute to antiviral and antitumor surveillance as well as inflammatory responses.
Figure 5 placeholder — Natural-killer-cell effects
Complement interactions
Complement interactions occur when administered cells, extracellular vesicles, proteins, or product surfaces encounter the complement system. Complement activation can opsonize particles or cells, promote inflammatory signaling, influence phagocytosis and clearance, and interact with coagulation pathways. MSCs express complement-regulatory molecules, yet complement-mediated injury or recognition can still occur depending on product and recipient factors. Complement activation-related effects may influence both efficacy and safety, particularly after intravascular administration. Mechanistic evaluation should distinguish complement activation, regulation, deposition, and downstream clinical consequences.
Figure 6 placeholder — Complement interactions
Clinical takeaway
Immunomodulation is not synonymous with generalized immune suppression. MSCs and EVs can alter multiple immune pathways, but the direction and magnitude of those effects depend on the product, inflammatory environment, dose, route, timing, and recipient.
Inflammatory licensing
MSCs can change their secretory and immunologic behavior after exposure to inflammatory signals such as interferon-gamma, tumor necrosis factor, or interleukin-1. This context-responsive behavior is often called licensing or priming and complicates attempts to assign one fixed mechanism to all MSC products.
Innate and adaptive immune integration
T cells, macrophages, dendritic cells, NK cells, complement, neutrophils, B cells, endothelium, and coagulation pathways interact rather than functioning as isolated modules. A measured change in one compartment may be secondary to another immune event.
Dose and timing
The same immunomodulatory signal can have different consequences at different stages of disease. Early suppression of inflammation may be beneficial in one context but impair host defense or repair in another.
Potency and biomarkers
A clinically useful immunomodulatory potency assay should reflect a mechanism relevant to the intended indication and should be quantitative, reproducible, and sensitive to meaningful product changes. Biomarkers can support mechanism but do not replace clinical endpoints.
Safety implications
Excessive or poorly targeted immune modulation can theoretically impair antimicrobial or antitumor surveillance, alter coagulation or complement responses, or produce unintended inflammatory effects. Safety must therefore be assessed rather than inferred from the term immunomodulatory.
Clinical interpretation
Changes in cytokines, immune-cell subsets, or in-vitro assays can support a mechanistic hypothesis but do not prove that immunomodulation caused a patient's clinical response. Mechanism and clinical effectiveness remain separate evidence questions.
Knowledge gaps
Human in-vivo immune mechanisms remain incompletely defined for many MSC and EV products. Product heterogeneity, recipient heterogeneity, limited tissue sampling, and inconsistent immune assays make cross-study generalization difficult.
Bottom-line evidence statement
Immunomodulation is a network effect involving both innate and adaptive immunity. Strong mechanistic evidence identifies the relevant immune pathway, demonstrates product-specific activity, links that activity to in-vivo biomarkers where feasible, and avoids equating preclinical immune effects with proven clinical benefit.
Additional controlled terminology
Proinflammatory signaling and anti-inflammatory signaling contribute to immunomodulation. Inflammatory licensing or priming can involve interferon-gamma, tumor necrosis factor, or interleukin-1 and may change prostaglandin E2 or indoleamine 2,3-dioxygenase activity. T-cell effects can involve a regulatory T cell, effector T cell, or Th17 cell. Macrophage biology includes efferocytosis, while dendritic-cell function involves antigen presentation, a costimulatory molecule, and potentially a tolerogenic state. A natural killer cell mediates cytotoxicity. Complement activation can produce opsonization and is moderated by a complement-regulatory molecule. Innate immunity and adaptive immunity interact, and an immune potency assay should measure product-relevant activity.