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Microbes & Immunity PTMs in Sepsis: Mechanisms and therapy

to the nucleus and drive pro-inflammatory gene the expression of pro-inflammatory cytokines, including
transcription. TNF-α-induced protein 8-like 2 (TIPE2) IL-1β and IL-6. Beyond inflammation, ERK1/2 supports
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and echinatin (Ecn) inhibit p65 nuclear translocation, adaptive immunity by regulating cell proliferation and
reducing inflammation and damage in sepsis. 26,27 In contrast, inhibiting apoptosis through the mitochondrial pathway.
the microRNA-210 host gene (MIR210HG) enhances This sustains T and B cell survival, enhancing host defense
IκBα phosphorylation and p65 nuclear translocation, against infection. 35,36 For instance, adrenomedullin
exacerbating sepsis-associated AKI. In addition, p65 2 (ADM2) stimulates ERK1/2 phosphorylation,
18
phosphorylation is a critical regulatory step; transcription promoting T and B cell proliferation and bolstering anti-
factor Kruppel-like factor 13 (KLF13) and astragaloside IV infective immunity. Similarly, artesunate enhances
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(AST) suppress p65 phosphorylation, mitigating sepsis- ERK1/2 phosphorylation in CD4 and CD8 T cells,
+
+
related myocardial injury and inflammation, 28,29 whereas reducing apoptosis and mitigating sepsis-induced
transcription coactivator PPARG coactivator 1 alpha immunosuppression. 38
(PGC-1α) promotes it, enhancing cytokine release and JNK, activated by stress signals such as oxidative stress
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inhibiting cardiomyocyte apoptosis. Parkinson’s disease and pro-inflammatory cytokines, phosphorylates c-Jun and
protein 7 (PARK7) protects against sepsis-induced AKI facilitates activating transcription factor 4 (ATF4) nuclear
by simultaneously blocking p65 nuclear translocation and translocation. These events drive the transcription of
phosphorylation. 31 inflammatory genes, amplifying the inflammatory response
The non-classical pathway is typically activated by in sepsis. JNK’s role in exacerbating inflammation makes
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specific stimuli, this pathway involves phosphorylation of it a critical target for therapeutic intervention.
p100, its processing to p52, and subsequently dimerization Several compounds have shown promise in modulating
with RelB for nuclear translocation and target gene ERK1/2 and JNK activity to attenuate sepsis-induced
transcription. SHP-1, a protein tyrosine phosphatase, inflammation. Tetrahydrocurcumin (THC) inhibits
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inhibits this pathway by suppressing p52 phosphorylation phosphorylation of both JNK and ERK1/2, reducing pro-
and nuclear translocation, dampening hyperinflammation inflammatory cytokine production and improving cardiac
and ALI in sepsis. SHP-1 also negatively regulates the function in sepsis models. Similarly, pinaverium bromide
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classical pathway by inhibiting the p50 phosphorylation (PVB) suppresses ERK1/2 and JNK phosphorylation in
and reducing p65 transcription and translation. 31
neutrophils by decreasing ROS production. This attenuates
Targeting dysregulated NF-κB signaling through inflammatory factor production and mitigates early-stage
molecules such as TIPE2, MIR210HG, KLF13, and SHP- sepsis-induced inflammation. In addition, PVB inhibits
1, alongside bioactive compounds such as Ecn and AST, phosphorylation of IκBα and p65, key components
offers promising anti-inflammatory strategies for sepsis of NF-κB signaling pathway, further reducing pro-
management. inflammatory responses in neutrophils. These findings
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highlight the therapeutic potential of targeting MAPK
3.2. MAPK signaling pathway pathways to balance inflammatory and immune responses
MAPKs, a family of serine/threonine kinases, regulate in sepsis.
proliferation, apoptosis, and inflammation, playing a MAPK p38 drives inflammatory factor expression by
pivotal role in sepsis pathogenesis through aberrant phosphorylating transcription factors such as ATF2 and
activation and subsequent overproduction of pro- C/EBP homologous protein (CHOP). It also directly
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inflammatory cytokines. The MAPK signaling pathway regulates NLRP3 inflammasome assembly, promoting
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encompasses four primary cascades: extracellular signal- IL-1β/IL-18 maturation and release. Anti-inflammatory
regulated kinase (ERK) 1/2, c-Jun N-terminal kinase mediators such as maresin-1 (MaR1) and fisetin suppress
(JNK), p38, and ERK5. These cascades are phosphorylated p38 MAPK phosphorylation, decreasing pro-inflammatory
and activated by upstream MAPK kinases to modulate factor expression and alleviating sepsis-induced organ
downstream targets. In sepsis, ERK1/2, JNK, and p38 are damage. 43,44 Peptide-proline isomerase Pin1 enhances
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the most extensively studied subtypes, with their activation NLRP3 inflammasome transcription and activation
intricately linked to the inflammatory response and disease through p38 MAPK phosphorylation, amplifying the
progression. inflammatory response and exacerbating organ damage in

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ERK1/2 is primarily activated by growth factors (e.g., sepsis. Furthermore, p38 MAPK enhances the activity of
epidermal growth factor) and inflammatory signals caspase-1, promoting gasdermin D cleavage and inducing
(e.g., TLR4) stimulation. Upon activation, ERK1/2 pyroptosis. In the pathogenesis of sepsis-associated AKI,
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phosphorylates transcription factor c-Fos, promoting the TLR4/MyD88 signaling pathway promotes p38 MAPK

Volume 2 Issue 3 (2025) 3 doi: 10.36922/MI025090016