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Microbes & Immunity Big data and DNN-based DTI model in CHP

inflammation and fibrosis. The canonical TGF-β signaling B-cell proliferation, suggesting the potential sensitivity of
cascade is initiated when the TGF-β ligand binds to the germinal center B cells to TGF-β and its role in limiting
type II TGF-β receptor (TGF-βR), which then recruits and the proliferation of fibroblastic cells in the lung and
forms a heteromeric complex with the type I TGF-βR. promoting apoptosis. 46
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This complex undergoes auto-phosphorylation of serine/ Overall, microbes such as Mycobacterium spp.,
threonine residues, allowing TGF-R1 to phosphorylate the Aspergillus fumigatus, Streptomyces spp., and Pseudomonas
suppressor of Mothers against decapentaplegic (SMAD)2 aeruginosa can interact with AKT1 signaling pathways,
and SMAD3 proteins. The activated SMAD proteins contributing to chronic inflammation and immune
dissociate from the SMAD anchor for receptor activation dysregulation seen in CHP. Their interaction with AKT1
and oligomerize with SMAD4. This SMAD complex helps sustain inflammation, prevent apoptosis, and
translocates to the nucleus, where it interacts with various promote tissue fibrosis, which are key pathological features
transcriptional co-regulators and other factors, modulating of CHP. SMAD proteins act as messengers that relay the
gene expression like DAXX. 42 signal from the extracellular TGF-β molecule to the
In normal epithelial cells, TGF-β signaling is typically interior of the cell, where it can influence various cellular
considered an anti-proliferative and pro-apoptotic signal. processes and have a crucial effect on the AKT1 signal
However, a critical step in the dysregulation of TGF-β pathway, including those involved in the pathogenesis of
signaling in CHP is the loss of this response. TGF-β can CHP.
exhibit pro-survival and anti-apoptotic effects, leading to
mitochondrial dysfunction through SMAD-dependent 3.2.2. The role of tumor necrosis factor signaling
activation. This subsequently triggers the death- pathway in the pathogenesis of CHP: A multifaceted
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associated protein 6 (DAXX)-mediated transformation regulator
growth factor, TNF receptor-associated factor (TRAF)- The TNF signaling pathway is a crucial mediator of various
dependent p38/JNK activation through non-SMAD physiological and pathological processes, including
mechanisms. TRAF proteins facilitate the activation cell proliferation, differentiation, apoptosis, immune
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of apoptosis signal-regulating kinase, which, in turn, response modulation, and inflammation induction.
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modulates downstream signaling pathways, including Microbes such as thermophilic actinomycetes, Aspergillus
MAPKs and PI3K-AKT. These interactions are crucial fumigatus, and endotoxin-producing bacteria are key
for regulating cellular responses to stress, inflammation, organic agents that influence TNF responses in CHP. They
and apoptosis, resulting in JNK-mediated cell death. are commonly found in environments related to farming,
DAXX can modulate the activity of MAPK kinases moldy buildings, and bird keeping. Chronic exposure
(MKKs), influencing downstream MAPK signaling to these antigens leads to persistent TNF-mediated
pathways involved in cellular processes such as stress inflammation, driving the progression of the disease.
response and programmed cell death. In addition to the TNF, a multifunctional pro-inflammatory cytokine,
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canonical SMAD pathway, TGF-β signaling can activate influences diverse processes, such as lipid metabolism,
the MAPK and PI3K signaling pathways, contributing coagulation, insulin resistance, and endothelial function.
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to the pathogenesis of CHP. The activation of these Initially discovered as a potential anticancer agent, TNF
pathways can promote cell survival, proliferation, and has since been recognized for its broader roles in cellular
migration, thus exacerbating disease indication and signaling. The TNF signaling cascade is initiated by the
the fibrotic response in the lungs. In the process of binding of cytokine TNF to its two receptors, TNF-R1 and
epithelial-mesenchymal transition (EMT), a crucial TNF-R2. TNF-R1 is ubiquitously expressed in all human
event in fibrosis, TGF-β-regulated fibroblast lineage tissues and is considered the main signaling receptor for
reprogramming, and cell migration depend on the p38 TNF-α, while TNF-R2 is primarily expressed in immune
MAPK signaling pathway. The kinetics and functions of cells and mediates limited biological responses. TNF-
the ERK/MAPK signaling pathway in response to TGF-β R2 can bind to both TNF-α and TNF-β. On TNF-α
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stimulation are tissue-specific, varying in epithelial cells, binding to TNFR1, a rapid formation of a cell-internal
fibroblasts, and cancer cells. The downstream signaling protein complex (termed complex I) occurs, comprising
induced by the binding of TGF-β to its serine/threonine receptor-interacting protein kinase 1 (RIPK1), TNF-
kinase receptors is also mediated by SMAD family R1 associated death domain (TRADD), and other
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members. For example, insulin signaling, including the signaling molecules. This protein complex activates the
activation of its downstream effector PI3K and AKT, can expression of inflammatory and survival genes. TRADD
inhibit TGF-β-mediated apoptosis. Furthermore, the acts as an adaptor molecule, binding to activated TNFR1
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exogenous TGF-β can suppress cytokine-induced human and recruiting additional signaling molecules into the

Volume 2 Issue 2 (2025) 94 doi: 10.36922/mi.4620