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A 20-Mer Peptide Derived from the Lectin Domain of SP-A2 Decreases Tumor Necrosis Factor Alpha Production during
Usir S Younis1, Hong Wei Chu2, Monica Kraft1,3,4
1Department of Medicine, University of Arizona, Tucson, Arizona, USA.
Abstract:
Human surfactant protein-A2 (hSP-A2) is a component of pulmonary surfactant that plays an important role in the lung's immune system by interacting with viruses, bacteria, and fungi to facilitate pathogen clearance and by downregulating inflammatory responses after an allergic challenge. Genetic variation in SP-A2 at position Gln223Lys is present in up to ∼30% of the population and has been associated with several lung diseases, such as asthma, pulmonary fibrosis, and lung cancer (M. M. Pettigrew, J. F. Gent, Y. Zhu, E. W. Triche, et al., BMC Med Genet 8:15, 2007, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-8-15; Y. Wang, P. J. Kuan, C. Zing, J. T. Cronkhite, et al., Am J Hum Genet 84:52-59, 2009, https://www.cell.com/ajhg/fulltext/S0002-9297(08)00595-8). Previous work performed by our group showed differences in levels of SP-A binding to non-live mycoplasma membrane fractions that were dependent on the presence of a lysine (K) or a glutamine (Q) at amino acid position 223 in the carbohydrate region of SP-A2. On the basis of these differences, we have derived 20-amino-acid peptides flanking this region of interest in order to test the ability of each to regulate various immune responses to live Mycoplasma pneumoniae in SP-A knockout mice and RAW 264.7 cells. In both models, the 20-mer containing 223Q significantly decreased both tumor necrosis factor alpha (TNF-α) mRNA levels and protein levels in comparison to the 20-mer containing 223K during M. pneumoniae infection. While neither of the 20-mer peptides (223Q and 223K) had an effect on p38 phosphorylation during M. pneumoniae infection, the 223Q-20mer peptide significantly reduced NF-κB p65 phosphorylation in both models. Taken together, our data suggest that small peptides derived from the lectin domain of SP-A2 that contain the major allelic variant (223Q) maintain activity in reducing TNF-α induction during M. pneumoniae infection.
Insights
Human surfactant protein-A2 (hSP-A2) genetic variants influence immune responses. Peptides derived from the 223Q variant of hSP-A2 effectively reduce inflammation during Mycoplasma pneumoniae infection.
Area of Science:
- Pulmonary immunology
- Molecular genetics
- Host-pathogen interactions
Background:
- Human surfactant protein-A2 (hSP-A2) is crucial for lung immunity, modulating pathogen clearance and inflammation.
- A common genetic variation (Gln223Lys) in SP-A2 is linked to lung diseases like asthma and pulmonary fibrosis.
- Previous studies indicated differential binding of SP-A2 variants to Mycoplasma, suggesting functional consequences.
Purpose of the Study:
- To investigate the immunomodulatory effects of SP-A2 peptides based on the Gln223Lys polymorphism.
- To determine if these peptides can regulate immune responses to live *Mycoplasma pneumoniae*.
Main Methods:
- Generation of 20-amino acid peptides flanking the 223Q and 223K variants of hSP-A2.
- Testing peptide efficacy in SP-A knockout mice and RAW 264.7 cells infected with *M. pneumoniae*.
- Measurement of TNF-α mRNA and protein levels, and phosphorylation of p38 and NF-κB p65.
Main Results:
- The 223Q-containing peptide significantly reduced TNF-α mRNA and protein levels during *M. pneumoniae* infection in both models.
- Neither peptide affected p38 phosphorylation.
- The 223Q-20mer peptide significantly reduced NF-κB p65 phosphorylation.
Conclusions:
- Small peptides derived from the hSP-A2 lectin domain, particularly the 223Q variant, retain immunomodulatory activity.
- These peptides show potential in reducing inflammatory responses, specifically TNF-α induction, during *M. pneumoniae* infection.
