Researchers appear to have found a novel way to sabotage fibrosis, the condition in which regenerative processes run awry with age and cells begin building scar-like structures that disrupt normal tissue function. The approach involves blocking TLR4 signaling. Fibrosis is a feature of the decline of many organs; liver, lung, kidney, heart, and so forth. If it can be turned off comparatively simply, that would produce noteworthy gains for the health of older individuals, even when the underlying causes of regenerative disarray are not addressed. The question is always whether or not there is a good way to interfere without also altering other important cellular processes, of course.
An interesting broader context for this TLR4 signaling inhibition is the growing evidence that suggests senescent cells to be a significant contributing cause of fibrosis. Senescent cells secrete a great many disruptive, inflammatory signal molecules, and that changes the behavior of surrounding cells, usually for the worse when that signaling persists for a long time. It may or may not be the case that senescent cells directly cause increased TLR4 signaling, but it is worthy of note that TLR4 deficient mice exhibit a reduced level of cellular senescence than their peers. There are some dots yet to be joined here.
Fibrosis, the hallmark of systemic sclerosis (SSc), is characterized by excessive production and persistent accumulation of collagens and other extracellular matrix (ECM) molecules in skin, lungs, and other internal organs. The process underlies a large number of fibrotic diseases that, in aggregate, account for a considerable proportion of deaths worldwide. With no effective therapy to date, fibrosis therefore represents a significant unmet global health need.
TLRs and related pattern-recognition receptors represent the first line of host defense against microbial pathogens. Cell surface receptors such as TLR4 and endosomal receptors such as TLR3 recognize extrinsic pathogen-associated molecule patterns (PAMPs) such as LPS and virus-derived nucleic acids. Significantly, TLRs also recognize damage-associated molecule patterns (DAMPs) that arise endogenously during various forms of noninfectious tissue injury. Regulated PAMP sensing by TLR4 has a unique requirement of myeloid differentiation 2 (MD2), an accessory receptor that interacts with TLR4 to form the signaling-competent receptor. The requirement for MD2 as an accessory pattern-recognition receptor for PAMPs appears to be unique for TLR4.
We recently demonstrated that particular DAMPs are markedly upregulated in fibrotic skin and lungs in patients with SSc and largely colocalize with TLR4-expressing myofibroblasts. In mice, genetic ablation of either of two DAMPs prominently associated with SSc resulted in markedly attenuated skin and lung fibrosis and enhanced fibrosis resolution, suggesting a fundamental pathogenic role for DAMP-TLR4 signaling in driving persistent organ fibrosis.
We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis.