Endogenous Transforming Growth Factor β1 Suppresses Inflammation and Promotes Survival in Adult CNS

Abstract

Transforming growth factor ␤1 (TGF␤1) is a pleiotropic cytokine with potent neurotrophic and immunosuppressive properties that is upregulated after injury, but also expressed in the normal nervous system. In the current study, we examined the regulation of TGF␤1 and the effects of TGF␤1 deletion on cellular response in the uninjured adult brain and in the injured and regenerating facial motor nucleus. To avoid lethal autoimmune inflammation within 3 weeks after birth in TGF␤1-deficient mice, this study was performed on a T-and B-cell-deficient RAG2Ϫ/Ϫ background. Compared with wild-type siblings, homozygous deletion of TGF␤1 resulted in an extensive inflammatory response in otherwise uninjured brain parenchyma. Astrocytes increased in GFAP and CD44 immunoreactivity; microglia showed proliferative activity, expression of phagocytosis-associated markers [␣X␤2, B7.2, and MHC1 (major histocompatibility complex type 1)], and reduced branching. Ultrastructural analysis revealed focal blockade of axonal transport, perinodal damming of axonal organelles, focal demyelination, and myelin debris in granule-rich, phagocytic microglia. After facial axotomy, absence of TGF␤1 led to a fourfold increase in neuronal cell death (52 vs 13%), decreased central axonal sprouting, and significant delay in functional recovery. It also interfered with the microglial response, resulting in a diminished expression of early activation markers [ICAM1 (intercellular adhesion molecule 1), ␣6␤1, and ␣M␤2] and reduced proliferation. In line with axonal and glial findings in the otherwise uninjured CNS, absence of endogenous TGF␤1 also caused an ϳ10% reduction in the number of normal motoneurons, pointing to an ongoing and potent trophic role of this anti-inflammatory cytokine in the normal as well as in the injured brain.

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

“…Furthermore, TGF-b1 pathway blockers efficiently blocked epileptogenesis in BBB breakdown and albumin models of epilepsy in mice and rats (11,16). Although TGF-b1 is a well-characterized immunoregulatory cytokine (19,20,25,(31)(32)(33)(34), it can also exert autoimmunity, glial activation, and brain inflammation (22,23,35,36). In the present study, we demonstrate that glial exposure to TGF-b1 induces a rapid and robust IL-6 upregulation at both the mRNA and protein levels.…”

Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25Highforkhead box P3+ regulatory T cells

“…Initial studies by Beyth et al [50] and Maccario et al [28] noted the induction of cells with phenotypic characteristics of Treg but did not involve functional studies of suppression. Li et al have shown similar findings using placental-derived multi-potent stem cells [51]; this observation is interesting, as it again highlights the similarities between immunomodulation at the feto-maternal interface [39] and those operating during repair [52][53][54].…”

S-Nitrosoglutathione Induces Ciliary Neurotrophic Factor Expression in Astrocytes, Which Has Implications to Protect the Central Nervous System under Pathological Conditions

“…Increasing evidence suggests that astrocytes play a central role in CNS functioning by regulating the immune responses under pathological conditions (3). Astrocytes behave differently in terms of the secretion of neurotrophic factors or inflammatory mediators under physiological and pathological conditions (51,52). Activation of astrocytes following CNS injury may have beneficial effects that include the monitoring and controlling of the extracellular water, pH, and ion homeostasis to promote the repair process.…”