Page 56 - MI-2-2

Microbes & Immunity Role of SRCR proteins in inflammation

in the inflamed intestinal mucosa of patients with Crohn’s patterns (DAMPs) that exacerbate symptoms, particularly
disease and ulcerative colitis, where its levels correlate with in the context of autoimmune arthritis. Conversely,
14
disease activity. This upregulation is mediated through in models such as aortic aneurysm, the administration
9
nuclear factor kappa B (NF-κB) activation in response to of an anti-CD5L antibody resulted in decreased CD5L
nucleotide-binding oligomerization domain-containing expression and improved survival rates by mitigating
protein 2 (NOD2) stimulation, emphasizing its significance inflammatory cytokines, reinforcing its context-dependent
in intestinal inflammation. Remarkably, patients with risk- actions. 15
promoting NOD2 mutations demonstrate significantly CD5L is also pivotal in modulating TLR activation
reduced DMBT1 levels in inflamed tissues compared to in monocytes, where it inhibits the production of pro-
those with wild-type NOD2. In addition, stimulation of inflammatory cytokines such as tumor necrosis factor (TNF),
Toll-like receptor 4 (TLR4) with lipopolysaccharide (LPS) IL-1β, and IL-6 whereas promoting the secretion of the
leads to an increase in DMBT1 expression, facilitated by anti-inflammatory cytokine IL-10. In addition, by binding
16
NF-κB activation. DMBT1 functions to inhibit bacterial to microbial cell wall components, CD5L signals immune
invasion and counteract LPS-induced TLR4-mediated cells to reduce inflammation and helps to restrain the pro-
NF-κB activation, acting as an extracellular homeostatic inflammatory activity of non-pathogenic Th17 cells. It
17
element that sustains a balanced immune response. This has also been shown to inhibit NOD-like receptor protein
10
dynamic indicates a self-regulatory mechanism in which 3 inflammasome activation, thereby decreasing airway
DMBT1 not only suppresses inflammation but also helps inflammation and Th2 immune responses. 18
combat infections, akin to the functions of secretory IgA.
This emphasizes DMBT1’s role in anti-inflammatory Nevertheless, the precise role of CD5L in inflammation
immune exclusion within an evolutionary context. 6 is complex and can lead to conflicting effects depending
on the disease context. One illustrative example of this
While information on the biological functions of SSC4D complexity is evident in experimental sepsis models, where
and SSC5D remains limited, emerging data indicate that the effects of recombinant CD5L (rCD5L) administration
both proteins may also have important contributions in vary significantly depending on the timing of delivery. When
resolving inflammation. SSC4D enhances macrophage- given concurrently with cecal ligation and puncture (CLP)
mediated phagocytosis and activates immune pathways, induction, increased mortality is observed, suggesting that
5
thereby supporting a balanced inflammatory response. early treatment may suppress inflammation to a degree that
Likewise, SSC5D plays a crucial role in regulating undermines the beneficial immune response. In contrast,
19
inflammation by downregulating pro-inflammatory administering rCD5L a few hours after sepsis onset shows
mediators, such as IL-8, effectively mitigating inflammatory protective effects by significantly reducing colony-forming
responses and reducing overall inflammation. 3 units (CFUs) in both the peritoneum and blood, thereby
Among the soluble SRCR proteins, CD5L stands out improving survival rates. However, if rCD5L were solely
20
for its significant anti-inflammatory potential. Primarily effective at inactivating pathogens, it would be expected
produced by macrophages, CD5L recognizes bacterial to perform better in the initial model when the microbial
cell wall components, enhancing antimicrobial responses load is low. Thus, the increased mortality seen with early
while simultaneously modulating inflammation. The administration indicates that its protective benefits
11
role of CD5L in clearing biological debris from dead or extend beyond direct pathogen control, highlighting the
necrotic cells has been recognized for some time. Recent significance of timing in its therapeutic application during
12
research has increasingly underscored its importance in sepsis.
regulating lipid biosynthesis and its involvement in various These observations emphasize the intricate and
inflammatory conditions, including atherosclerosis, obesity, multifaceted roles of CD5L, highlighting its critical
11
nephropathy, and autoimmune diseases. In addition, function in modulating inflammatory responses beyond
CD5L has been identified as one of the proteins with reduced merely controlling pathogens. Transcriptomic profiling
levels in coronavirus disease 2019 (COVID-19) patients of CD5L-knockout mice in the context of CLP revealed
experiencing severe disease. As such, CD5L may serve as a pronounced inflammatory response, reflecting the
13
a valuable biomarker for assessing inflammation severity dysregulated immune responses often seen in sepsis.
20
and as a potential therapeutic target to mitigate excessive Collectively, these findings suggest that CD5L may evolve
immune activation in critically ill COVID-19 patients. into a valuable therapeutic agent in sepsis, in which
Studies suggest that CD5L exerts anti-inflammatory the timing of administration is crucial for managing
effects by lowering levels of inflammatory cytokines and inflammation while preserving essential early immune
aiding in the clearance of damage-associated molecular responses. Ultimately, the anti-inflammatory properties of

Volume 2 Issue 2 (2025) 48 doi: 10.36922/mi.5741